Taxane synthesis method and intermediates

ABSTRACT

A process for the preparation of a composition having the formula:  
                 
 
     in which a compound having the formula:  
                 
 
     is treated with a base and a silylating agent.

REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on U.S. Provisional Application SerialNo. 60/056,210, filed Aug. 21, 1997.

[0002] This invention was made with government support under NIH Grant#CA 42031 awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

SUMMARY OF THE INVENTION

[0003] The present invention is directed to a process for thepreparation of baccatin III, taxol, docetaxel and their analogs fromborneol (1) and camphor (2), commonly known articles of commerce.

[0004] Processes for the total synthesis of taxol and other tetracyclictaxanes from commodity chemicals have been proposed. For example, inU.S. Pat. No. 5,405,972, Holton et al. disclose a process for thesynthesis of taxol and other tetracyclic taxanes from β-patchoulineepoxide which, in turn, may be obtained from borneol (1) and camphor(2). Yields obtained by these processes, however, leave some room forimprovement.

[0005] Leriverend and Conia (Bull. Soc. Chim. Fr., 1970, 1060) observedthat diol 4 (which is readily prepared from either camphor or borneol)when heated to 220° C. for a period of one hour rearranged to provide amixture of ketones 5 and 6 in a ratio of 1:2. Ketone 5 is of greatutility in the synthesis of taxanes.

[0006] The preparation of diol 4 and ketones 5 and 6 is illustrated inReaction Scheme 1.

[0007] Briefly, therefore, the present invention is directed to aprocess for the preparation of ketone 5 in relatively high yield andwithout contamination with ketone 6. The process comprises treating acompound having the formula:

[0008] with a base and a silylating agent to form a compound having theformula:

[0009] The present invention is further directed to a process forconverting ketone 5 into taxol, docetaxel, and other taxanes. Accordingto this process, a derivative of ketone 5 having the formula:

[0010] is treated with an alkyl metal species, preferablytert-butyllithium, or is treated with a Lewis acid, preferably TMSOTf,in the presence of a tertiary amine base, preferably triethylamine, toform a compound having the formula:

[0011] wherein P₂ is hydrogen or a hydroxyl protecting group. Theprocess for converting ketone 5 into taxol, docetaxel, and other taxanesmay additionally comprise treating a compound having the formula:

[0012] with a Lewis acid, preferably TMSOTf, in the presence of atertiary amine base, preferably triethyl amine, to form a compoundhaving the formula:

[0013] wherein P₂ and P₁₀ are independently hydrogen or a hydroxylprotecting group.

[0014] The present invention is additionally directed to the followingintermediates having the formulae

[0015] wherein P₂, P₉, P₁₀ and P₁₃ are independently selected fromhydrogen and hydroxy protecting groups. Compounds containing one or morehydroxy protecting groups can be converted to their hydroxy groupanalogs by removing such hydroxy protecting groups using standardmethods. The compounds identified above are key intermediates in thesynthesis of baccatin III, 1-deoxy baccatin III, taxol, 1-deoxy taxol,docetaxel, 1-deoxy docetaxel, and the analogs of these compounds.

[0016] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention provides a process for the preparation ofketone 5 in high yield relative to its isomer 6. When diol 4 is treatedwith a base in the presence of a silylating agent, ketone 5 can beobtained in greater than 95% yield. The base employed is preferablystronger than an alkoxide base. More preferably, the base is a hydridebase or an amide base. Still more preferably, the base is potassiumhydride or potassium hexamethyldisilazide. The base is preferablynonreactive with the silylating agent selected for the reaction.

[0018] Silylating agents for the reaction include those compoundscomprising the group —SiR₁R₂R₃ wherein R₁, R₂ and R₃ are independentlysubstituted or unsubstituted C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,monocyclic aryl or monocyclic heteroaryl. Such silylating agents mayfurther comprise a hydride or triflate group, for exampletri(hydrocarbyl)silyl halides and tri(hydrocarbyl)silyl triflates. Thehydrocarbon moieties of these silylating agents may be substituted orunsubstituted and preferably are substituted or unsubstituted alkyl oraryl. Trialkylsilyl halides are more preferred with alkyl groupscontaining from one to four carbon atoms. Still more preferably, thesilylating agent is triethylsilyl chloride. Ethereal solvents arepreferred for the reaction, with THF being the more preferred solvent.

[0019] While the temperature at which the reaction is carried out is notnarrowly critical, the temperature may affect the overall yield of thereaction. Preferably, the temperature of the reaction is maintainedbelow about 50° C.; more preferably, the temperature is maintained at orbelow about 25° C.; even more preferably, the temperature initially ismaintained at or below about 0° C. and subsequently is maintained at orbelow about 25° C. As illustrated in the Examples, these latterconditions produced ketone 5 in 96% yield.

[0020] Likewise, the sequence of addition of diol 4, the base and thesilylating agent is flexible. For example, diol 4, the base and thesilylating agent may be combined at the beginning of the process andreacted in essentially a single step, or these reagents may be combinedas described in the Examples.

[0021] The reagents for the foregoing reaction (as well as the reagentsfor the reactions subsequently discussed in this application) arepreferably provided in approximately stoichiometric amounts, althoughvarious ratios of the reagents can be effectively employed.

[0022] Without being bound to any specific theory, it is believed basedupon the evidence to date that the base operates to deprotonate the twohydroxy groups of diol 4. The less-sterically-hindered deprotonatedhydroxy group (which corresponds to the front hydroxy group of thestructure of diol 4 illustrated in Reaction Scheme 1) then reacts withthe silylating agent to form a protected hydroxy group. The otherdeprotonated hydroxy group (which corresponds to the rear hydroxy groupof the structure of diol 4 illustrated in Reaction Scheme 1) does notreact with the silylating agent. The protected diol 4 then undergoes theoxy-Cope rearrangement to provide a nine-membered ring containing asilyl enol ether and an enolate. Upon the addition of water the enolateis protonated and the subsequent aldol condensation is directed by theposition of the silyl enol ether to provide ketone 5.

[0023] Ketone 5 can be further converted to other useful taxanesynthetic intermediates as shown below.

[0024] As shown in reaction scheme 2, treatment of ketone 5 with anamide base, preferably an alkali metal amide base and more preferablyLHMDS, in an ethereal solvent, preferably THF, and then with ahydroxylating agent, preferably an oxaziridine and more preferablyphenylsulfonyl oxaziridine, provides allylic alcohol 7. Allylic alcohol7 in the presence of an epoxidizing agent, preferably a peroxy acid andmore preferably m-chloroperbenzoic acid, is converted to epoxide 8.Epoxide 8 can be reduced stereoselectively to diol 9 (P₂=H), using ahydride reducing agent, preferably a borohydride and more preferablysodium borohydride. The secondary hydroxyl group of 9 can be protectedwith any of a variety of protecting groups, using standard methods fortheir attachment. Treatment of 9 with a Lewis acid in the presence of atertiary amine base, preferably triethyl amine, causes its rearrangementto give 10. In general, the Lewis acids that can be used includetriflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB,VIIB, VIII, IIIA, IVA, lanthamides, and actinides (American ChemicalSociety format), with a preferred Lewis acid being TMSOTf. The secondsecondary hydroxyl group of 10 can be protected with any of a variety ofprotecting groups so that P₁₀ and P2 may be the same or different andreadily chemically distinguishable from each other.

[0025] Alternatively, as shown in reaction scheme 3, treatment of ketone5 with a hydride reducing agent, preferably a borohydride and morepreferably sodium borohydride, in the presence of a Lewis acid,preferably a lanthamide metal halide or triflate and more preferably asamarium or cerium halide, selectively furnishes allylic alcohol 11,which undergoes epoxidation from the α-face in the presence of peracidssuch as m-chloroperbenzoic acid (or hydroperoxides such as tert-butylhydroperoxide in the presence of metal catalysts or promoters such astitanium (+4) or vanadium (+5) to give epoxide 12 (P₂=H). The secondaryhydroxyl group of 12 can be protected with any of a variety ofprotecting groups, using standard methods for their attachment. Theepoxide ring of 12 can be opened to provide allylic alcohol 13, usingeither an alkyl metal species, preferably an alkyllithium and morepreferably tert-butyllithium, or a Lewis acid, in the presence of atertiary amine base, preferably triethylamine. In general the Lewisacids that can be used include triflates and halides of elements ofgroups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthamides,and actinides (American Chemical Society format), with a preferred Lewisacid being TMSOTf. Allylic alcohol 13 again undergoes epoxidation fromthe a-face in the presence of peracids such a m-chloroperbenzoic acid(or hydroperoxides such as tert-butyl hydroperoxide in the presence ofmetal catalysts or promoters such as titanium (+4) and vanadium (+5)) togive epoxide 14. Treatment of 14 with a Lewis acid in the presence of atertiary amine base, preferably triethyl amine, causes its rearrangementto give 15. In general the Lewis acids that can be used includetriflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB,VIIB, VIII, IIIA, IVA, lanthamides, and actinides (American ChemicalSociety format), with a preferred Lewis acid being TMSOTf. The secondsecondary hydroxyl group of 15 can be protected with any of a variety ofprotecting groups so that P₁₀ and P₂ may be the same or different andreadily chemically distinguishable from each other.

[0026] It should be noted that 15 is the C(2) epimer of 10.

[0027] Alcohols 10 and 15 undergo the “epoxy alcohol fragmentation” toprovide 16 and 17, respectively (P₁₃=H), which possess the taxane ABring structure. The epoxy alcohol fragmentation is carried out by firsttreating the substrate with an epoxidizing agent, then warming theproduct in the presence of a metal salt. The epoxidizing agentpreferably is a peroxy acid such as m-chloroperbenzoic acid (or ahydroperoxide such as tert-butyl hydroperoxide in the presence of metalcatalysts or promoters such as titanium (+4) or vanadium (+5)). Thepreferred metal salt is a halide or alkoxide of a group IA, IIA, IIIB,IVB, VB, VIB, VIIB or VIII metal, with a preferred metal salt beingtitanium tetraisopropoxide. More preferably, the epoxidizing agent istert-butyl hydroperoxide in the presence of titanium tetraisoprepoxide.The C(13) secondary hydroxyl group of 16 and 17 can be protected withany of a variety of protecting groups so that P13, P₁₀ and P₂ may be thesame or different and readily chemically distinguishable from eachother.

[0028] Treatment of 17 (P₂, P₁₀, and P₁₃=hydroxyl protecting groups)with a potassium base and methyl iodide provides 18, having the βconfiguration of the newly introduced methyl group, as shown in reactionscheme 4. The preferred potassium base is potassiumhexamethyldisilazide, the preferred solvent is tetrahydrofuran, and thepreferred temperature is −5° C. to 0° C. Treatment of 18 (P₂, P₁₀, andP₁₃=hydroxyl protecting groups) with a base followed by 4-pentenalprovides 19 (p₂, P10, P₁₃=hydroxyl protecting groups and P₇=H).Preferred bases are chosen from lithium and magnesium amides withbromomagnesium diisopropyl amide (BMDA) being a more preferred base. Thepreferred solvent is tetrahydrofuran and the preferred temperature isbetween −45° C. and 0° C. The C7 hydroxyl group of 19 can be protectedwith a variety of hydroxyl protecting groups. For example, treatment of19 with phosgene and pyridine then ethanol, followed by selectiveremoval of P₂, provides an intermediate (19, P₂=H, P₇=CO₂Et, P₁₀=TES,and P₁₃=TBS) used in the total synthesis of baccatin III and taxol (See,e.g., J. Amer. Chem. Soc., 1994, 116, 1597-1600).

[0029] Also, oxidation of 10 (P₁₀=H) and 15 (P₁₀=H) with any of avariety of standard oxidizing agents provides, respectively, 21 and 20,shown in reaction scheme 5. Preferred oxidizing agents are chromiumbased reagents. Pyridinium dichromate is a particularly preferredoxidizing agent. Reduction of 21 and 20 with hydride reducing agentsprovides 23 (P₁₀=H) and 22 (P₁₀=H), respectively. Preferred reducingagents are chosen from the group of borohydrides and aluminohydrideswith lithium aluminum hydride being a more preferred reducing agent. Thenewly introduced secondary hydroxyl group of 23 (P₁₀=H) and 22 (P₁₀=H)can be protected with any of a variety of protecting groups so that P₁₀and P₂ may be the same or different and readily chemicallydistinguishable from each other. Alcohols 23 and 22 undergo the “epoxyalcohol fragmentation” to provide 25 and 24 respectively (P₁₃=H), whichpossesses the taxane AB ring structure. The C(13) secondary hydroxylgroup of 24 and 25 can be protected with any of a variety of protectinggroups so that P₁₃, P₁₀ and P₂ may be the same or different and readilychemically distinguishable from each other.

[0030] Ketone 20 may be further oxidized to provide a more advancedtaxane synthetic intermediate, as shown in reaction scheme 6. Treatmentof 20 with an amide base and a tri(hydrocarbon)silyl halide or triflateprovides an intermediate silyl enol ether, which is treated directlywith a peracid to give 26 (P₉=H). The preferred amide base is an alkalimetal amide base and more preferably is LDA. The preferredtri(hydrocarbon)silyl halide or triflate is a trialkylsilyl chloridewith triethyl silyl chloride being particularly preferred. The preferredperacid may include peroxy carboxylic acids with m-chloroperbenzoic acidbeing particularly preferred. The C(9) secondary hydroxyl group of 26can be protected with any of a variety of protecting groups so that P₉,P₁₀ and P₂ may be the same or different and readily chemicallydistinguishable from each other. Reduction of 26 with hydride reducingagents provides 27 (P₁₀=H). Preferred reducing agents are chosen fromthe group of borohydrides and aluminohydrides; the most preferredreducing agent is lithium aluminum hydride. The newly introducedsecondary hydroxyl group of 27 (P₁₀=H) can be protected with any of avariety of protecting groups so that P₁₀, P₉ and P₂ may be the same ordifferent and readily chemically distinguishable from each other.Alcohol 27 undergoes the “epoxy alcohol fragmentation” to provide 28(P₁₃=H), having the taxane AB ring structure. The C(13) secondaryhydroxyl group of 2 can be protected with any of a variety of protectinggroups so that P₁₃, P₁₀, P₉ and P₂ are the same or different and readilychemically distinguishable from each other. Treatment of 28 with anamide base, preferably an alkali metal amide base and more preferablyLHMDS, and a methyl halide or sulfonate, preferably methyl iodide, in anethereal solvent, preferably THF, provides 29, which has been used as anintermediate in the total synthesis of C(1) deoxy baccatin III (See,e.g., PCT Patent Application Serial No. PCT/US97/07569, InternationalPublication No. WO 97/42181).

[0031] Definitions

[0032] As used herein, the term “LHMDS” means lithiumhexamethyldisilazide; “KHMDS” means potassium hexamethyldisilazide;“LDA” means lithium diisopropyl amide; “BMDA” means bromomagnesiumdiisopropyl amide; “PSO” means phenylsulfonyl oxaziridine; “THF” meanstetrahydrofuran; “mCPBA” means meta-chloroperbenzoic acid; “TES” meanstriethylsilyl; “TMS” means trimethylsilyl; “Tf” means —SO₂CF₃; “TEA”means triethylamine; “t-BuLi” means tert-butyllithium; “PDC” meanspyridinium dichromate; “LAH” means lithium aluminum hydride; “TBHP”means tert-butyl hydroperoxide; “TTIP” means titanium tetraisoprepoxide;“protected hydroxy” means —OP wherein P is a hydroxy protecting group;and “hydroxy protecting group” includes, but is not limited to, acetalshaving two to ten carbons, ketals having two to ten carbons, ethers suchas methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl,trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl,tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers suchas trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether,triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such asbenzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetylsuch as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl;and carbonates including but not limited to alkyl carbonates having fromone to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having fromone to six carbon atoms and substituted with one or more halogen atomssuch as 2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates having from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl, protecting groups may be found in“Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley andSons, 1981, and Second Edition, 1991.

[0033] The “hydrocarbon” moities described herein are organic compoundsor radicals consisting exclusively of the elements carbon and hydrogen.These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. Thesemoieties also include alkyl, alkenyl, alkynyl, and aryl moietiessubstituted with other aliphatic or cyclic hydrocarbon groups, such asalkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1to 20 carbon atoms.

[0034] The alkyl groups described herein are preferably lower alkylcontaining from one to six carbon atoms in the principal chain and up to20 carbon atoms. They may be straight or branched chain and includemethyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may besubstituted with aliphatic or cyclic hydrocarbon radicals orhetero-substituted with the various substituents defined herein.

[0035] The alkenyl groups described herein are preferably lower alkenylcontaining from two to six carbon atoms in the principal chain and up to20 carbon atoms. They may be straight or branched chain and includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and thelike. They may be substituted with aliphatic or cyclic hydrocarbonradicals or hetero-substituted with the various substituents definedherein.

[0036] The alkynyl groups described herein are preferably lower alkynylcontaining from two to six carbon atoms in the principal chain and up to20 carbon atoms. They may be straight or branched chain and includeethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They maybe substituted with aliphatic or cyclic hydrocarbon radicals orhetero-substituted with the various substituents defined herein.

[0037] The aryl moieties described herein contain from 6 to 20 carbonatoms and include phenyl. They may be hydro-carbon or heterosubstitutedwith the various substituents defined herein. Phenyl is the morepreferred aryl.

[0038] The heteroaryl moieties described are heterocyclic compounds orradicals which are analogous to aromatic compounds or radicals and whichcontain a total of 5 to 20 atoms, usually 5 or 6 ring atoms, and atleast one atom other than carbon, such as furyl, thienyl, pyridyl andthe like. The heteroaryl moieties may be substituted with hydrocarbon,heterosubstituted hydrocarbon or hetero-atom containing substituentswith the hetero-atoms being selected from the group consisting ofnitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens.These substituents include lower alkoxy such as methoxy, ethoxy, butoxy;halogen such as chloro or fluoro; ethers; acetals; ketals; esters;heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protectedhydroxy; acyl; acyloxy; nitro; amino; and amido.

[0039] The heterosubstituted hydrocarbon moieties described herein arehydrocarbon moieties which are substituted with at least one atom otherthan carbon, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude lower alkoxy such as methoxy, ethoxy, butoxy; halogen such aschloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such asfuryl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy;nitro; amino; and amido.

[0040] The acyl moieties described herein contain hydrocarbon,substituted hydrocarbon or heteroaryl moieties.

[0041] The alkoxycarbonyloxy moieties described herein comprise lowerhydrocarbon or substituted hydrocarbon moieties.

[0042] The following example illustrates the invention.

EXAMPLES

[0043] (−)-(1S)-Camphor (2).

[0044] To a vigorously stirred solution of 600 g (3:89 mol) of(−)-borneol in 1.5 L of glacial acetic acid at 0° C. was added 7.5 L ofhousehold bleach (Chlorox™) over a period of 1 h. After 30 min the solid(800 g) was collected by filtration and dissolved in 2 L of hexane. Thesolution was washed with saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄ and concentrated to give 570 g (96%) of camphor.

[0045] 2: mp: 178-180° C.; [α]_(D) ²⁵=−39 (c=3.0, EtOH), ¹H NMR seeTable; ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 9.20, 19.10, 19.74, 27.02,29.90, 43.05, 43.25, 46.73, 57.64, 219.46.

500 MHz ¹H NMR Data in CDCl₃ for Camphor (2)

[0046] 2

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 2.09 4.6(2β) 2β(1.0) 3.6(14β) 2α 1.8517.4(2β) 2β(6.5) 2β 2.35 17.4(2α) 1β(0.9); 2α(5.7); 16(1.2) 3.6(1β)3.1(14β) 13α 1.41 12.7(13β) 13β(6.8) 9.3(14α) 3.8(14β) 13β 1.6812.7(13α) 14β(1.7); 13β(10.9); 17(1.9); 18(.7) 12.6(14β) 4.4(14α) 14α1.34 12.3(14β) 14β(7.4) 9.6(13α) 4.4(13β) 14β 1.96 12.3(14α) 13β(0.8);14α(9.6); 17(1.3) 12.6(13β) 3.8(13α) 3.6(1β) 3.1(2β) 16 0.84 s 2β(1.0);1β(0.6) 17 0.97 s 1β(0.1); 14β(0.5); 13β(0.4) 18 0.92 s 13β(0.4)

[0047] (+)-Camphorquinone (3).

[0048] To a solution of 370 g (2.43 mol) of (−)-camphor in 300 mL ofacetic anhydride at 25° C. was added 500 g (4.5 mol) of SeO₂. Thesolution was heated to reflux at 150° C. with vigorous mechanicalstirring for 4 h, then filtered through coarse filter paper. The residuewas washed with ten 200 mL portions of ethyl acetate. The ethyl acetatesolution was combined with the acetic anhydride filtrate andconcentrated to a volume of 500 mL. The solution was cooled to 0° C. togive a bright yellow solid which was collected by filtration. Thefiltrate was concentrated to a volume of 300 mL and cooled to give asecond batch of yellow product. The remaining residue was cooled to −10°C., 15% NaOH was added until the solution was basic, and the solutionwas extracted with two 1 L portions of ethyl acetate. The collectedyellow product was dissolved in ethyl acetate extract and the solutionwas washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄and concentrated to give 378 g (94%) of camphorquinone (3).

[0049] 3: mp: 210-203° C.; [α]_(D) ²⁵=+95.8 (c=4.0, toluene); ¹H NMR(400 MHz, CDCl₃) δ (ppm): 0.94 (s, 3H), 1.06 (s, 3H), 1.11 (s, 3H), 1.64(m, 2H), 1.91 (m, 1H), 2.17 (m, 1H), 2.62 (d, 5.2). ¹³C NMR (100 MHz,CDCl₃) δ (ppm): 8.71, 17.37, 21.05, 22.25, 29.91, 42.54, 57.96, 58.62,202.79, 204.77.

[0050] Diol 4.

[0051] To 800 mL of a 1.0M solution of vinylmagnesium bromide in THF at0° C. was added a solution of 60 g (0.36 mol) of (+)-camphorquinone (3)in 360 mL of THF. The mixture was warmed to 25° C., and after 12 h 10 mLof deionized water was added dropwise. After 5 min, 10 mL of 5% HCl wasadded dropwise. The solution was diluted with 1 L of ethyl acetate, theorganic layer was separated, washed with saturated aqueous NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated to give a brown solid. Thesolid was recrystallized from hexane at −78° C. to give 60.5 g of diol4. The mother liquor was purified by chromatography to yield anadditional 12 g of the diol. The total yield was 72.5 g (91%).

[0052] 4: mp: 84-85° C.; [α]_(D) ²⁵=+12 (c=1.4, CHCl₃); ¹H NMR (500 MHz,CDCl₃) δ (ppm): see Table; ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 10.06,22.49, 23.00, 23.13, 30.45, 49.46, 54.32, 56.26, 83.56, 85.23, 114.40,114.71, 140.56, 141.39; IR (CHCl₃), υ (cm⁻¹): 3607, 3550, 3090, 1620;Mass Spec. (CI) 223.6 (M⁺+1), 205.4.

500 MHz ¹H NMR Data in CDCl₃ for Diol 4

[0053] 4

Proton δ(ppm) J(Hz) n.O.e.(%) 3 6.25 16.6(8β) 10α(0.65); 8β(3.5);14α(4.7) 10.2(8α) 10α 6.15 16.6(9β) 3α(1.1); 9α(4.4); 13α(7.1) 10.2(9α)9β 5.38 16.6(10α) 8α + 9α(10.1); 3OH + 11OH(1.3) 1.6(9α) 8β 5.3616.6(3α) 1.6(8α) 8α 5.19 10.2(3α) 3α + 10α(2.8); 8β + 9β(10.9) 1.6(8β)9α 5.19 10.2  1.6 OH 2.73 8β + 9β(2.1); 16(4.2) OH 2.68 1β 1.84 4.7(14b)8β(0.5); 14β(2.62); 16(0.8); 17(1.1) 14β 1.67 14.2 1(1.8); 14α(10.6);13β(1.1); 12.5 17(5.5)  4.7  3.1 14α 1.56 m 3α(2.8); 8α(0.7); 1β(1.0);14β(2.1); 13α 1.52 m 10α(7.1); 13β(10.6) 13β & Me16 1.36 m 1β(1.5);14β(2.4); 13α(41); 17(2.6); 18(1.5) Me17 0.91 1β(1.0); 14β(2); 13β +16(3.9) Me18 0.82 10α(1.2); 9β(0.3); 11OH(0.4); 13β + 16(2.1)

[0054] Ketone 5.

[0055] To a suspension of 20 g (0.5 mol) of KH in 400 mL of THF at −78°C. was added a solution of 43 g (0.19 mol) of diol 4 in 300 mL of THFAfter 2 h 39 mL (0.23 mol) of triethylsilyl chloride was added. Aftertwo additional hours the solution was warmed to 25° C. After 8 h 50 mlof deionized H₂O was added dropwise. After 1 h, the solution waspartitioned between 1 L of hexane and 200 mL of deionized H₂O. Theorganic layer was separated, washed with two 100 mL portions of ofbrine, dried over Na₂SO₄, and concentrated to give a solid mass. Thesolid was repeatedly recrystallized from hexanes at −78° C. to give 35 gof enone 5. The mother liquor was purified by flash chromatographyeluting with 10% ethyl acetate in hexanes to give an additional 3 g of5. The combined yield of 5 was 38 g (96%).

[0056] 5: mp 95-97° C.; [α]_(D) ²⁵=−7 (c=4.25, CHCl₃); ¹H NMR (500 MHz,CDCl₃), see Table; ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 15.1, 18.9, 21.9,23.2, 23.9, 28.7, 33.9, 35.9, 49.3, 51.4, 62.0, 135.4, 172.4, 201.3;Mass Spec. (CI) 205.4 (M⁺+1).

500 MHz ¹H NMR Data in CDCl₃ for Enone 5

[0057] 5

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 2.43 7.5(14β) 14β(1.9); 17(2.5);16(0.8) 10β + 10α + 8α 2.56 m 18(1.5); 9α + 9β(3.0) 8β 2.48 m 9α +9β(5.2) 9α + 9β 1.93 m 10β + 10α + 8α(4.4); 8β(2,6) 13β 1.87 12.5(13α)14β(0.4); 13α(10.3); 10.4(13β) 18(1.3); 17(1.8) 2.9(14α) 13α 1.6012.5(13β) 10α(0.5); 13β(15.2); 11.5(14α) 14α(3.4); 18(0.8) 3.2(13α) 14β2.18 12.7(14β) 1β(4.0); 13β(3.5); 14α(18.0) 10.4(13β) 7.5(1β) 17(2.2);16(1.0) 3.2(13α) 14α 1.40 12.7(14β) 1β(1.7); 14β(16.8); 13α(1.4)11.5(13(α) 2.9(13β) Me18 1.11 10β(2.3); 13β(1.1); 13α(0.3) Me17 0.931β(1.7); 14β(1.1), 13β(1.4); 18(0.6); 16(1.0) Me16 0.87 9β(0.3);1b(0.7); 18(0.9); 17(0.2)

[0058] Ketone 7.

[0059] To a solution of 2.0 g (9.8 mmol) of enone 5 in 150 mL of THF(150 ml) at 0° C. was added 2 g (10 mmol) of KHMDS. After 1 h thesolution was cooled to −78° C. and a solution of 3.8 g (14.5 mmol) ofN-phenylsulfonyl phenyloxaziridine in 150 mL of THF was added. After 2 hthe mixture was warmed to 25° C. and partitioned between 200 mL of ethylacetate and saturated aqueous NaHCO₃. The organic layer was separated,washed with brine, dried over Na₂SO₄ and concentrated to give a solidmass. The crude product was purified by chromatography with 20% ethylacetate in hexanes to give 1.52 g (6.9 mmol, 70% yield) of 7 as an oil.

[0060] 7: mp 70-71° C.; [α]_(D) ²⁵=−14.1; ¹H NMR (400 MHz, CDCl₃); δ(ppm): 0.64 (s, 3H); 0.97 (s, 3H); 1.15 (s, 3H); 1.79 (s, 1H), 1.88 (m,1H), 1.99 (m, 1H), 2.07 (m, 3H), 2.19 (m, 1H), 2.22 (ddd, J=16.4, 8.4,3.3, 1H), 2.43 (d, J=7.7, 1H), 2.58 (m, J=8.5, 2.2, 1H), 5.69 (dd,J-3.3, 2.2, 1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 16.79, 21.03, 23.03,25.12, 28.13, 34.06, 35.99, 46.89, 47.60, 62.53, 85.63, 127.72, 151.56,212.72.

[0061] Epoxy alcohol 8.

[0062] To a solution of 1.0 g (4.5 mmol) of hydroxyketone 7 in 50 mL ofhexane at 25° C. was added 1.8 g (65% purity, 6.8 mmol ) of mCPBA. After1 h the mixture was diluted with 150 mL of ethyl acetate and 30 mL of10% aqueous NaS₂O₃ was added. The mixture was then partitioned between200 mL of ethyl acetate and 150 mL of saturated aqueous NaHCO₃. Theorganic layer was separated, washed with brine, dried over Na2SO₄ andconcentrated under vacuum to give 1.05 g (4.44 mmol, 98%) of 8 as asolid.

[0063] 8: mp 65-67° C.; [α]_(D) ²⁵=−83.5° (c=1.15, CHCl₃); ¹H NMR (500MHz, CDCl₃), see Table; ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 13.91, 20.21,23.07, 24.40, 24.87, 33.01, 34.32, 45.33, 45.62, 61.84, 66.86, 75.75,82.75, 208.43.

400 MHz HNR Data for Epoxide 8

[0064] 8

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 2.52 7.3(14β) 14β(1.1); 17(0.8) 8α 2.7114.9(8β) 9α(−0.3); 9β(2.1); 8β(11.2) 11.4(9β) 4.5(9α) 8β 1.58 14.9(8α)8α(39.4); 9β(0.9) 9.4(9α) 5.9(9β) 9α 2.11 15.0(9β) 10β(1.1); 9β(11.2);13β(2.1) 9.4(8β) 4.5(8α) 9β 1.70 15.0(9α) 10β(1.2); 8α(2.8); 9α(9.7);11.4(8α) 5.9(8β) 2.3(10β) 10β 3.55 2.3(9β) 9α(0.9); 9β(2.0); 18(3.6);16(0.4) 13α 2.35 12.9(13β) 14α(0.9); 13β(12.6) 9.2(14α) 4.5(14β) 13β1.75 15.0(14β) 13α(11.0); 14β(3.9); 172.1); 18(0.4) 12.9(13α) 4.2(14α)14α 2.26 13.2(14β) 14β(9.8) 9.2(13α) 4.2(13β) 14β 2.01 15.0(13β)1β(2.8); 14α(12.0); 13β(2.7); 172.3) 13.2(14α) 7.3(1β) 4.5(13α) 16 0.7810β(0.6); 8β(0.6); 1β(0.8); 9β(1.2); 17(15) 17 0.99 1β(1.4); 14β(1.3);13β(1.1); 18(1.0); 16(1.3) 18 0.82 10B(2.0); 13b(1.2); 17(1.3)

[0065] Epoxide 9 (P₂=H).

[0066] To a solution of 4.52 g (20.5 mmol) of hydroxyketone 7 in 150 mLof methanol at 0° C. was added 1.55 g (41.0 mmol) of NaBH₄. After 1 h 25mL of 1M NaOH solution was added. The mixture was diluted with 200 ml ofethyl acetate. The organic layer was washed with water, saturatedaqueous ammonium chloride, saturated aqueous NaHCO₃ and brine, driedover Na₂SO₄ and concentrated to give 4.53 g (19 mmol, 100%) of epoxide 9(P₂=H) as a white solid.

[0067] 9 (P₂=H): mp 122-124; [α]D²⁵=+28 (c=1.7, MeOH); ¹H NMR (500 MHz,CDCl₃), see Table; ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 13.38, 20.92,24.41, 25.09, 25.95, 32.12, 35.48, 44.22, 45.25, 52.28, 65.70, 74.32,78.15, 81.43. MW=238.33, Analysis Calc. for C₁₄H₂₂O₃ C:70.56, H:9.30;Found C:70.64, H:9.32.

500 MHz ¹H NMR Data in CDCl₃ for Epoxide 9 (P₂=H)

[0068] 9

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 1.95 7.7(14β) 2α(1.8); 17(0.9) 2.8(2β)2α 3.85 2.8(1β) 1β(0.4); 14α(0.7) 8α 1.35 14.1(8β) 8β(11.9); 9α(1.2)8.6(9α) 3.9(9β) 8β 2.56 14.1(8α) 9β(1.0); 8α(11.7); 5.3(9β) 2.1(9α) 9α2.07 14.6(9β) 9β(12.8); 8α(1.6) 8.6(8α) 2.1(8β) 9β 1.76 14.6(9α)10β(0.9); 8β(0.9); 9α(10.2) 5.3(8β) 3.9(8α) 1.9(10β) 10β 3.48 1.3(9β)9β(1.0); 18(1.2) 13α 2.18 14.6(14α) 13α(6.2); 17(0.6); 18(0.5) 13.3(13β)8.0(14β) 13β 1.49 13.3(13α) 13β(2.6) 9.6 4.4 14α 1.83 m 14β 1.89 m 161.05 s 10β(0.5); 17(0.6); 18(1.4) 17 0.92 s 1β(0.6); 14β(0.5); 13β(0.8);18(0.3) 18 0.73 s 10β(1.0); 13β(0.6); 16(0.4); 17(0.7)

[0069] Alkene 10 (P₂=P₁₀=H). To a solution of 0.74 g (3.1 mmol) ofepoxide 9 (P₂=H) in 50 mL of dichloromethane at −78° C. was added 4.5 mL(31 mmol) of triethylamine and 1.9 mL (10 mmol) of TMSOTf in that order.The mixture was warmed to −30° C. and after 2 h 2 mL of anhydrous MeOHwas added. After 10 min the mixture was concentrated and to the residuewas added 10 mL of acetonitrile, 10 mL (124 mmol) of pyridine, and 3 mL(86.7 mmol) of aqueous HF. This mixture was stirred at 25° C. for 5 hand diluted with 150 mL of ethyl acetate. The solution was washed twicewith 100 mL of saturated aqueous NaHCO₃ and brine. The aqueous layerswere combined and extracted twice with 100 mL of ethyl acetate. Theorganic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated. The residue was diluted with 150 mL of hexane andconcentrated for azeotropic removal of excess pyridine to give 0.73 g(3.06 mmol, 99%) of alkene 10 (P₂=P₁₀=H) as a white powder.

[0070] 10(P₂=P₁₀=H): mp 212-215° C.; [α]_(D) ²⁵=+59.9 (c=3.7, MeOH); ¹HNMR (500 MHz, CDCl₃), see Table; ¹³C NMR (100 MHz, CDCl₃) δ (ppm):23.31, 26.26, 27.58, 31.13, 32.51, 38.34, 43.33, 53.21, 67.93, 75.72,89.66, 99.74, 123.72, 141.12.; Mass spec. (CI) 354 (M+1, 100), 336 (44),317 (26) 222 (25), 204 (50); MW=238.33, Analysis Calc. for C₁₄H₂₂O₃C:70.56, H:9.30; Found C:70.26, H:9.13.

500 MHz H NMR Data in CDCl₃ for Alkene 10 (P₂=P₁₀=H)

[0071] 10

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 1.66 5.6(14β) 2α(4.0); 14β(2.1);16(1.6); 17(0.3) 2β 3.83 s OH(2.3); 14α; OH(2.4); 1β(1.9); OH(3.9) 8α1.80 12.2(8β) 2α(2.2); 8β(16.2); 9α(3.3) 7.7(9α) 3.5(9β) 8β 2.2612.2(8α) 10β(1.3); 8α(14.9); 16(4.1) 8.3(9α) 3.9(9β) 9α 2.10 12.1(9β)10β(0.5); 9β(13.4); 8α(1.7) 8.6(8β) 7.7(9α) 5.9(10β) 9β 2.34 12.1(9α)10β(2.5); 9α(12.5); 8β(0.7); 16(1.5) 5.6(10β) 3.9(8β) 3.5(8α) 10β 4.465.9(9α) 9β(2.3); 8β(0.5); 16(3.7); 17(0.7) 5.6(9β) 13 5.49 m 14β(1.9);14α + 18(4.7) 14α 2.02 17.9(14β) 13(1.9); 2α(4.4); 14β(13.8) 14β 2.4317.9(14α) 13(2.5); 14α + 18(17.1); 1β(3.1); 17(2.6) 5.6(1β) 1.7(18) 161.19 s 10β(3.7); 9β(1.6); 8β(3.5); 1β(2.8); 17(0.8) 17 1.05 s 13(0.1);10β(0.6); 14β(1.4); 1β(0.8); 16(1.1) 18 2.01 1.3(13) 13(2.9) 1.7(14β)

[0072] Alkene 10 (P₂=H, P₁₀=TES).

[0073] To a solution of 0.7 g (2.94 mmol) of triol 188 in 5 mL ofdichloromethane at 25° C. was added 1.2 ML (8.6 mmol) of triethylamineand 0.5 mL (2.92 mmol) of triethylsilyl chloride. After 10 h 0.3 mL (1.7mmol) of triethylsilyl chloride and 1 mL (7.2 mmol) of triethylaminewere added. After 1 h 0.06 mL (1.6 mmol) of anhydrous methanol wasadded. After 10 min reaction mixture was diluted with 150 mL of ethylacetate, washed with saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄ and concentrated to give 1.03 g (2.92 mmol, 99%) of alkene 10(P₂=H, P₁₀=TES).

[0074] 10 (P₂=H, P₁₀=TES): [α]D₂₅=(c=, MeOH); ¹H NMR (500 MHz, CDCl₃);¹³C NMR (100 MHz, CDCl₃) δ (ppm): 4.92, 6.84, 23.44, 25.42, 27.75,31.02, 32.10, 38.73, 43.62, 53.43, 66.82, 74.22, 89.20, 98.46, 122.23,142.38.; MW=238.33, Analysis Calc. for C₂₀H₃₆O₃Si, C:68.13, H: 10.29;Found: C:68.15, H: 10.21.

[0075] Alcohol 11. To a cooled solution of 23.11 g (98 mmol) of iodinein 250 ml of THF (−45° C.) was added by small portions 14.74 g (98 mmol)of Samarium, the mixture was stirred for 30 min (yellow solid: Sm₁₃)then 15 min at room temperature. The enone 5 (10 g, 49 mmol) was addedas a solid and the resulting mixture was stirred for 30 min. 3.7 g (98mmol) of NaBH₄.was added by small portions at −20° C. After 3 h, themixture was poured into a mixture of 10 g of NaHCO₃ and 50 ml of asaturated aqueous solution of Na₂S2O₃ and stirred for 1 h. The mixturewas diluted by 100 ml of AcOEt, filtered through a cake of celite andconcentrated to lead to a mixture of the ,allylic alcohol (20%) and theα-allylic alcohol 11 (80%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃),δ (ppm): 0.87 (s, 3H, 16Me), 0.90 (s, 3H, 17Me), 0.91 (s, 3H, 18Me),1.34 (d, 1H), 1.60 (m, 4H), 1.81 (m, 3H), 2.23 (m, 2H), 2.32 (m, 1H),2.44 (m, 1H), 4.41 (brs, 1H, H₂O).

[0076] Epoxide 12 (P₂=H).

[0077] The above crude oil was dissolved in 122 ml of dichloromethaneand 368 ml of hexane at −15° C. and NaHCO₃ in powder (12.35 g, 147 mmol)was introduced followed by 21.14 g (73.5 mmol) of mCPBA. The reactionmixture was stirred for 2 h 30 at 0° C. then filtered. The organic layerwas washed by 25 ml of a 1:1 solution of NaHCO₃ and Na₂S₂O₃, dried overNa₂SO₄ and concentrated to give a mixture of unreacted Fallylic alcoholand the desired α-epoxy-alcohol 12 (97%) as a colorless oil.

[0078] The crude oil was dissolved in 50 ml of hexane and cooled to −78°C., the crystallized a-epoxy-alcohol 12 was filtered and dryed. 8.5 g(78% over 3 steps) of α-epoxy-alcohol 12 was obtained. m.p. 98-100° C.;¹H NMR (500 MHz, CDCl₃), δ (ppm): 0.82 (s, 3H, 16Me), 0.87 (s, 3H,17Me), 1.03 (s, 3H, 18Me), 1.33 (m, J=16.1, 8.3 Hz, 1H, H9α), 1.41 (m,1H, H13β), 1.42 (m, 1H, H14β), 1.53 (ddd, J=13.3, 5.9, 3 Hz, 1H, H8β),1.57 (m, 1H, H10β), 1.58 (m, J=5.9 Hz, 1H, H9β), 1.78 (ddd, J=6.8, 5.9,1.5 Hz, 1H, H1), 1.82 (d, J=9.8 Hz, 1H, 2-OH), 1.90 (m, 1H, H₁₀α), 1.95(m, 1H, H14α), 1.96 (m, 1H, H13α), 2.21 (dd, J=13.3, 8.3 Hz, 1H, H8α),4.00 (dd, J=9.8, 5.9 Hz, 1H, H2β).

[0079] To the mother liquor was added 21.4 g (244 mmol) of MnO₂ at 0°C., the mixture was stirred at 0° C. for 1 h and 2 h at roomtemperature. The reaction mixture was then filtered through a cake ofsea sand and concentrated to afford 2 g (20%) of recovered enone 5.

[0080] Epoxide 12 (P₂=PMB).

[0081] A solution of 1 g (4.5 mmol) of the above a-epoxy-alcohol 12(P₂=H) in 10 ml of DMF was added to 500 mg (13.5 mmol) of dry NaH. Theresulting mixture was stirred for 30 min then 672 μl (4.95 mmol) ofPMBCl was introduced. After 2 h 30, the reaction mixture was cooled to−15° C., quenched by addition of 1 ml of methanol then poured into 10 mlof a saturated aqueous solution of NaHCO₃ and extracted twice with 50 mlof hexane/ethyl acetate (1:1). The organic layer was washed with 5 ml ofbrine, dried over Na₂SO₄ and concentrated. A flash chromatography(hexane/ethyl acetate 9:1) yielded to 1.496 g (97%) of the epoxide 12(P₂=H). ¹H NMR (500 MHz, CDCl₃), δ (ppm): 0.77 (s, 3H, 16Me), 0.87 (s,3H, 17Me), 1.02 (s, 3H, 18Me), 1.37 (dd, J=8, 7 Hz, 1H, H9α), 1.39 (dd,J=10, 4.8 Hz, 1H, H13β), 1.45 (dddd, J=13.1, 9.9, 7.7, 3.2 Hz, 1H,H₁₄β), 1.49 (m, 1H, H8β), 1.51 (m, 1H, H10β), 1.55 (m, J=8 Hz, 1H, H9β),1.85 (dd, J=7.7, 5.8 Hz, 1H, H1), 1.93 (m, J=12.8 Hz, 1H, H10α), 1.93(dd, J=13.1, 1.9 Hz, 1H, H14α), 1.98 (dd, J=10, 1.9 Hz, 1H, H13α), 2.18(dd, J=13.4, 7 Hz, 1H, H8α), 3.74 (d, J=5.8 Hz, 1H, H2β), 3.81 (s, 3H,OMe), 4.50 (d, J=11.8 Hz, 1H, Hb), 4.59 (d, J=11.8 Hz, 1H, Ha), 6.87 (d,J=8.7 Hz, 2H, H2′), 7.29 (d, J=8.7 Hz, 2H, H1′).

[0082] General Procedure for Synthesis of Epoxides 14 (P2=H or PMB).

[0083] To a refluxing solution of 1 g (4.5 mmol) of α-epoxide 12 in123.5 ml of hexane was added 26.5 ml (45 mmol) of a 1.7M solution ofthutyllithium in hexane through the condenser. The resulting mixture wasrefluxed for 2 h then cooled to −10° C. and 3 ml of methanol was slowlyadded. The mixture was concentrated, the yellow solid was dissolved in25 ml of ethyl acetate and 2 ml of water and stirred for 15 min at roomtemperature. The mixture was dried over Na₂SO₄, filtered and the solidwas washed twice with 25 ml of ethyl acetate. The combined organiclayers were concentrated and the crude 13 was used for the second stepwithout farther purification. ¹H NMR of diol 13 (300 MHz, CDCl₃): δ(ppm) 0.64 (s, 3H, 18Me), 0.97 (s, 3H, 16Me), 1.15 (s, 3H, 17Me), 1.42(ddd, J=14.2, 9.1, 9 Hz, 1H, H8α), 1.53 (m, 1H, H130), 1.65 (m, 1H,H14β), 1.72 (dddd, J=14.8, 10.1, 9, 1.4 Hz, 1H, H9β), 1.86 (dd, J=6.8,3.4 Hz, 1H, H1), 2.03 (ddd, J=13.3, 9.4, 4 Hz, 1H, H14α), 2.11 (ddd,J=14.8, 9.1, 2 Hz, 1H, H9α), 2.12 (s, 1H, 3-OH), 2.20 (m, 1H, H13α),2.20 (ddd, J=14.2, 10.1, 2 Hz, 1H, H8β), 2.91 (d, J=9.4 Hz, 1H, 2-OH),3.40 (d, J=1.4 Hz, 1H, H10β), 3.76 (dd, J=9.4, 3.4 Hz, 1H, H2β).

[0084] The crude was dissolved in 50 ml of dichloromethane and 2.6 g (9mmol) of mCPBA in 45 ml of dichloromethane were added. After 14 h, themixture was diluted with 55 ml of dichloromethane and washed with 50 mlof a 1:1 saturated aqueous solution of NaHCO₃ and Na₂S₂O₃. The aqueouslayer was extracted twice with 50 ml of dichloromethane and the combinedorganic layers were dried over Na₂SO₄ and concentrated. Flashchromatography (hexane/ethyl acetate 1:1) afforded the epoxy-alcohol 14as a colorless oil, yield 59% for P2=H. ¹H NMR of the2,3-dihydroxy-epoxide 14 (500 MHz, CDCl₃): δ (ppm) 0.72 (s, 3H, 18Me),0.86 (s, 3H, 16Me), 0.95 (s, 3H, 17Me), 1.42 (ddd, J=14.2, 9.1, 9 Hz,1H, H8α), 1.53 (m, 1H, H13β), 1.65 (m, 1H, H14β), 1.72 (dddd, J=14.8,10.1, 9, 1.4 Hz, 1H, H9β), 1.86 (dd, J=6.8, 3.4 Hz, 1H, H1), 2.03 (ddd,J=13.3, 9.4, 4 Hz, 1H, H14α), 2.11 (ddd, J=14.8, 9.1, 2 Hz, 1H, H9α),2.12 (s, 1H, 3-OH), 2.20 (m, 1H, H13α), 2.20 (ddd, J=14.2, 10.1, 2 Hz,1H, H8β), 2.91 (d, J=9.4 Hz, 1H, 2-OH), 3.40 (d, J=1.4 Hz, 1H, H10β),3.76 (dd, J=9.4, 3.4 Hz, 1H, H2′).

[0085] Or as a white solid, yield 25% for P2=PMB, m.p. 88-90° C., seeNMR below.

[0086] Epoxide 14 (P₂=PMB).

[0087] A solution of 1.41 g (5.9 mmol) of the above epoxy-diol 14 (P₂=H)in 25 ml of DMF was added to 660 mg (17.88 mmol) of dry NaH. Theresulting mixture was stirred for 30 min then 808 pLI (5.9 mmol) ofPMBCl was introduced. After 1 h, the reaction mixture was quenched byaddition of 2 ml of methanol and diluted by 100 ml of hexane/ethylacetate (1:1). The organic layer was washed with 20 ml of water, driedover Na₂SO₄ and concentrated. Flash chromatography (hexane/ethyl acetate8:2) afforded 1.93 g (91%) of product 14 (P2=PMB) as white solid. m.p.88-90° C.; ¹H NMR (500 MHz, CDCl₃), δ (ppm): 0.72 (s, 3H, 18Me), 0.84(s, 3H, 16Me), 0.97 (s, 3H, 17Me), 1.50 (ddd, J=13.1, 11.8, 4.1 Hz, 1H,H13β), 1.56 (m, 1H, H8α), 1.58 (m, 1H, H9β), 1.67 (ddd, J=13.3, 7, 4.5Hz, 1H, H14β), 1.82 (dd, J=13.3, 8.7 Hz, 1H, H8β), 1.99 (dd, J=7, 3.2Hz, 1H, H1), 2.05 (dd, J 13.1, 8.7 Hz, 1H, H9α), 2.17 (ddd, J=13.3, 9.7,4.1 Hz, 1H, H14α), 2.42 (ddd, J=13.1, 9.7, 4.5 Hz, 1H, H13α), 2.89 (s,1H, 3-OH), 3.25 (d, J=1 Hz, 1H, H10β), 3.50 (d, J=3.2 Hz, 1H, H2β), 3.81(s, 3H, OMe), 4.44 (d, J=11.3 Hz, 1H, Hb), 4.63 (d, J=11.3 Hz, 1H, Ha),6.87 (d, J=8.6 Hz, 2H, H2′), 7.26 (d, J=8.6 Hz, 2H, H1′);

[0088]¹³C NMR (100 MHz, CDCl₃), δ (ppm): 13.4, 19.1, 21.4, 24.5, 24.7,32.6, 37.3, 43.9, 44.6, 47.7, 55.3, 62.4, 70.8, 72.2, 78.4, 79.6, 113.8,129.5, 130.2, 139.3.

[0089] Alkene 15 (P₂=PMB.

[0090] P₂=H). To a solution of epoxide 12 (P₂=PMB) (15.87 g, 46.4 mmol)in 375 ml of dichloromethane and triethylamine (64.5 ml, 464 mmol) at−78° C. was slowly added 25.2 ml (139.2 mmol) of TMSOTf. The reactionmixture was stirred at −35° C. for 14 h. Methanol (20 ml) was added toquench the reaction and the temperature was allowed to rise at 25° C.The volatils were removed under reduced pressure and the residue waspartly dissolved in 500 ml of hexane, filtered on celite. The organiclayer was concentrated to give 18.7 g of crude material which was useddirectly in the next step. ¹H NMR (500 MHz, CDCl₃), δ (ppm): 0.10 (s,9H, 3-TMS), 0.65 (s, 3H, 18Me), 0.91 (s, 3H, 16Me), 1.00 (s, 3H, 17Me),1.53 (m, 1H, H13β), 1.64 (dt, J=13.8, 8.7 Hz, 1H, H8α), 1.78 (m, 1H,H14β), 1.84 (dd, J=6.9, 3.3 Hz, 1H, H1), 1.98 (m, 1H), 2.20 (m, 1H),2.22 (m, 1H), 2.30 (m, 1H), 2.47 (m, 1H), 3.44 (d, J=2.9 Hz, 1H, H₂β),3.81 (s, 3H, OMe), 4.45 (d, J=11.6 Hz, 1H, Hb), 4.58 (d, J=11.6 Hz, 1H,Ha), 5.34 (dd, J=3.3, 1.8 Hz, 1H, H 10β), 6.87 (d, J=8.4 Hz, 2H, H2′),7.29 (d, J=8.4 Hz, 2H, H1′).

[0091] To the mixture of 18.7 g of the above crude material in 460 ml ofa 1:3 mixture of dichloromethane/hexane at 0° C. were added 17.15 g(69.6 mmol) of mCPBA and 5.85 g (139.2 mmol) of NaHCO₃. The reactionmixture was stirred at room temperature for 4 h and filtered. The solidwas washed with 50 ml of hexane and the organic layer was washed twicewith 50 ml of a 1:1 aqueous solution of saturated NaHCO₃ and saturatedNa₂S₂O₃, dried over Na₂SO₄ and concentrated to lead to 20.2 g of acolorless oil.

[0092] To a solution of 20.2 g of the above crude oil in 375 ml ofdichloromethane and 64.5 ml (464 mmol) of triethylamine at −45° C. wasslowly added 25.2 ml (139.2 mmol) of TMSOTf. The reaction mixture wasthen stirred at −25° C. for 3 h. Methanol (20 ml) was added to quenchthe reaction and the temperature was allowed to rise at roomtemperature. The volatils were removed under reduced pressure and theresidue was partly dissolved in 500 ml of hexane, filtered on celite.The organic layer was concentrated to give 20 g of crude product.Crystallization in acetonitrile at −10° C. gave 18 g of a white solid.m.p. 98-100° C.;

[0093]¹H NMR (400 MHz, C₆D₆), δ (ppm): 0.13 (s, 9H, CH₃ 10-TMS), 0.24(s, 9H, CH₃ 3-TMS), 0.94 (s, 3H, 16Me), 1.27 (s, 3H, 17Me), 1.33 (dt,J=13, 5.6 Hz, 1H, H8β), 1.83 (brt, J=5.2 Hz, 1H, H1), 2.12 (dd, J=13,6.3 Hz, 1H, H8α), 1.98 (ddd, J=11.7, 6.3, 5.6 Hz, 1H, H9α), 2.03 (ddq,J=17.5, 3.1, 2.3 Hz, 1H, H14β), 2.21 (dt, J=2.3, 2, 2 Hz, 3H, 18Me),2.33 (m, 2H, H9EH14α), 3.28 (s, 3H, OMe), 3.70 (dd, J=5.2, 0.6 Hz, 1H,H2β), 4.10 (d, J=10.8 Hz, 1H, Hb), 4.23 (d, J=10.8 Hz, 1H, Ha), 4.40(dd, J=10.5, 6.3 Hz, 1H, H10β), 5.34 (m, 1H, H13), 6.80 (d, J=8.6 Hz,2H, H2′), 7.22 (d, J=8.6 Hz, 2H, H1′).

[0094] To a solution of 18 g of the above solid in 50 ml of acetonitrileand 20 ml of pyridine was added 30 ml of a 48% aqueous solution of HF at0° C. The mixture was stirred at room temperature for 5 h, poured into asolution of 50 ml of ethyl acetate and NaHCO₃ solid was added till noreaction was observed. After filtration, the volatils were removed underreduced presure and a plug chromatography (hexane/ethyl acetate 1:1)yielded to 12.57 g (75% over 4 steps) of alkene 15 (P₂=PMB, P₁₀=H) as anoil. ¹H NMR (500 MHz, CDCl₃), δ (ppm): 1.04 (s, 3H, 16Me), 1.13 (s, 3H,17Me), 1.47 (d, J=7.7 Hz, 1H, 10-OH), 1.68 (dddd, J=15, 7.7, 2.2, 1.9Hz, 1H, H8β), 1.96 (m, 1H, H1), 1.97 (dt, J=2.2, 1.6, 1.6 Hz, 3H, 18Me),2.01 (ddq, J=17.9, 2.9, 2.2 Hz, 1H, H14β), 2.10 (dt, J=11.5, 7.7, 7.7Hz, 1H, H9α), 2.12 (m, J=2.2 Hz, 1H, H8α), 2.25 (ddt, J=11.5, 6, 2.2,2.2 Hz, 1H, H9β), 2.39 (ddq, J=17.9, 2.9, 1.6 Hz, 1H, H14α), 3.15 (d,J=1.9 Hz, 1H, 3-OH), 3.81 (s, 3H, OMe), 3.82 (d, J=6.1 Hz, 1H, H2β),4.34 (d, J=11.2 Hz, 1H, Hb), 4.42 (td, J=7.7, 7.7, 6 Hz, 1H, H10,), 4.60(d, J=11.2 Hz, 1H, Ha), 5.38 (m, J=1.6 Hz, 1H, H13), 6.87 (d, J=8.6 Hz,2H, H2′), 7.26 (d, J=8.6 Hz, 2H, H1′); ¹³C NMR (100 MHz, CDCl₃): δ (ppm)22.3, 25.3, 25.8, 27.9, 38.6, 39.2, 39.7, 50.2, 55.2, 66.1, 72.1, 75.3,83.4, 90.2, 113.7, 123.4, 129.2, 130.6, 140.5, 159.1.

[0095] Ketone 16 (P₂=P₁₃=H, P₁₀=TES):

[0096] To a methylene chloride (3 ml) solution of alkene 10 (P₂=H,P₁₀O=TES) (0.298 g, 0.845 mmol) at 0° C. was added Ti(iOPr)₄ (0.75 ml,2.53 mmol) and a 2.0 M hexane solution of t-butyl hydroperoxide (1.06ml, 2.11 mmol) and stirred at 0° C. for 30 min. To the reaction mixturewas added dimethylsulfide (0.8 ml, 11 mmol) and stirred at 0° C. for 1 hand warmed to 25° C. for 20 min. The reaction mixture was poured into aflask of THF (40 ml) and stirred vigorously while adding deionized water(0.25 ml) over for 15 min to form a white precipitate. The solution wasdried over MgSO₄ and filtered through a bed of celite and concentrated.To a methylene chloride (10 ml) solution of the crude reaction mixturewas added flash silica gel (1 g) and the mixutre was heated under refluxwith a 60° C. silicon oil bath for 3 h. The reaction mixture wasfiltered through a fritted funnel and washed with ethyl acetate andconcentrated to give ketone 16 (P₂=P₁₃=H, P₁₀=TES) (0.31 g, 0.841 mmol,99%) as a white solid.

[0097] 16 (P₂=P₁₃=H, P₁₀=TES): m: 111-112° C.; [α]D²⁵=(c=, MeOH); ¹³CNMR (100 MHz, CDCl₃) δ (ppm): 4.87, 6.83, 13.15, 27.29, 33.06, 34.79,36.47, 37.38, 39.01, 53.18, 69.64, 76.10, 138.35, 157.86, 200.12,215.95.

[0098] 500 MHz ¹H NMR Data in CDCl₃ for Ketone 16 (P₂=P₁₃=H, P₁₀=TES)

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 1.94 8.0(14β) 2α(3.1); 14β(1.8);16(0.4); 17(1.4) 1.92(2α) 2α 4.10 1.92(1β) 13OH(1.6); 2OH(3.8); 1β(4.0);14α(6.0) 8α 1.82 13.9(8β) 8β(19.6); 9α(4.2) 5.3(99β) 8β 3.35 13.9(8α)10β(3.5); 8β(27.9); 16(6.9) 12.1(9α) 2.8(9β) 9α 2.57 12.1(8β) 9β +18(15.2) 10.4(10β) 9β 1.97 m 10β(3.5); 9α(18.5) 10β 4.58 10.4(9α)8β(1.6); 9β(3.5); 16(6.5) 5.3(9β) 13β 3.98 11.8(14β) 14β(3.9);13OH(1.0); 18(2.3); 17(3.6) 9.5(13OH) 14α 1.75 15.9(14β) 2α(9.7);14β(18.7); 14β 2.91 15.9(14α) 13β(8.8); 1β(5.1); 14β(24.7); 17(5.3)11.8(13β) 8.0(1β) 16 1.53 s 10β(3.8); 8β(1.8); 1β(1.3); 17(1.4) 17 1.02s 13β(2.6); 14β(2.8); 1β(1.6); 16(1.4) 18 1.96 s CH₃-TES 0.95 7.9CH₂-TES 0.59 7.9

[0099] Ketone 17 (P₂=P₁₃=H, P₁₀=TES) by Epoxy-Alcohol Fragmentation of10 (P₂=H, P₁₀=TES):

[0100] To a methylene chloride (0.5 ml) solution of alkene 10 (P₂=H,P10=TES) (50 mg, 0.142 mmol) at 0° C. was added Ti(iOPr)₄ (0.17 ml, 0.57mmol) and a 2.0 M hexane solution of t-butyl hydroperoxide and stirredat 0° C. for 30 min. To the reaction mixture was added dimethylsulfide(0.17 ml, and stirred at 0° C. for 1 h and warmed to 25° C. for 20 minthen heating to reflux with a 60° C. silicon oil bath for 12 h. Thereaction mixture was poured into a flask of THF (20 ml) and stirredvigorously while adding deionized water (0.15 ml) over for 15 min togive a white precipitate. The solution was dried over MgSO₄ and filteredthrough a bed of celite and concentrated. Filtration of the reactionmixture through a plug silica gel gave ketone 17 (P₂=P₁₃=H, P₁₀=TES) (51mg, 97%) as a white powder.

[0101] Ketone 17 (P₂₌P₁₃=H, P₁₀=TES) by Epimeriztion of Ketone 16(P₂=P₁₃=H, P₁₀=TES):

[0102] To a methylene chloride solution of ketone 16 (P₂=P₁₃=H, P₁₀=TES)(12 mg, 0.033 mmol )was added Ti(iOPr)₄ (0.05 ml, 0.17 mmol) and heatedto reflux with a 60° C. silicon oil bath for 6 h. The reaction mixturewas poured into a flask of THF (20 ml) and stirred vigorously whileadding deionized water (0.05 ml) over for 15 min to give a whiteprecipitate. The solution was dried over MgSO₄ (1 g) and filteredthrough a bed of celite and concentrated. Purification of the reactionmixture by flash silica gel chromatography eluting with 75% ethylacetate in hexanes gave ketone 17 (P₂=P₁₃=H, P₁₀=TES) (11 mg, 92%) as awhite powder. 195a: mp: 76-80° C.; [α]_(D) ²⁵=+16.1 (c=1.0, CHCl₃).

500 MHz ¹H NMR Data in CDCl₃ for Ketone 17 (P₂=P₁₃=H, P₁₀=TES)

[0103]

Proton δ(ppm) J(Hz) n.O.e.(%) 1β 2.17 6.5(14β) 2β(3.5); 14β(3.2);16(2.4); 17(3.3) 6.0(2β) 2β 4.52 7.6(2OH) 2OH(0.8); 8β(2.6); 1β(2.7);6.0(1β) 16(2.9) 2OH 2.91 7.6(2β) 2β(2.4); 14α(5.5); 13OH(−4.7) 8α 2.3012.9(8β) 8β(16.7); 9β(4.3); 9α(1.7) 5.3(9α) 3.4(9β) 8β 2.61 14.5(9β)10β + 2β(8.8); 8α(24.1); 9β(4.0); 12.9(8β) 16(4.0) 3.0(9α) 9α 2.4915.7(9β) 9β + 18(25.5) 5.4(10α) 5.3(8α) 3.0(8β) 9β 1.98 15.7(9α)9α(15.5) 14.5(8β) 9.0(10β) 3.4(8α) 10β 4.53 9.0(9β) 8β(1.9); 16(5.6)5.4(9α) 13β 4.04 10.9(13OH) 14β(3.1); 18(1.9); 13OH(2.0) 10.4(14β)17(2.9) 3.0(14α) 0.7(18) 13OH 1.81 10.9(13β) 13β(1.1); 14α + 18(5.8) 14α1.98 16.4(14β) 2OH(6.3); 14β(18.5); 13OH(2.0) 3.0(13β) 14β 2.4616.4(14α) 13β(3.5); 1β(2.6); 23.2); 17(4.8) 10.4(13β) 6.5(1β) 16 1.49 s10β + 2β(9.5); 8β(2.2); 1β(2.4); 17(1.9) 17 1.12 s 13β(2.0); 14β(1.9);1β(1.5); 18 1.96 0.7(13β) 16(1.0) CH₃-TES 0.96 7.6(CH₂-TES) CH₂-TES 0.607.6(CH₃-TES)

[0104] Ketone 17 (P₂=PMB, P₁₃=H, P₁₀=TES). To a stirred solution ofalkene 15(P_(hd)=PMB, P₁₀=H) (7.31 g, 20.39 mmol) in methylene chloride(70 ml) and hexanes (70 ml) was added at room temperature buffersolution pH 8 (50 ml), then mCPBA (8.8 g at 60%, 30.6 mmol). After 4 hrsat room temperature, saturated sodium bisulfite solution (50 ml) wasadded. The white precipitate was filtered through celite. The aqueouslayer was extracted with ethyl acetate. The combined organic extractswere washed with saturated sodium bisulfite solution, saturated sodiumbicarbonate solution then brine, dried over sodium sulfate and filtered.The solvent was removed under reduced pressure to afford 7.42 g (97%) ofcrude epoxide as a white solid. The white solid obtained was generallysubjected to the next reaction without further purification. A samplefrom a related experiment was purified via flash chromatography (6:4Hex-EtOAc). Mp 114° C.; ¹H (C₆D₆, 400 MHz, VR-1-257) δ 0.54 (3H, s,16-Me), 0.67 (3H, s, 17-Me), 1.38 (1H, ddd, J=15.7, 6.8, 4.9 Hz,H_(14β)), 1.46 (1H, t, J=6.8 Hz, H₁), 1.72 (3H, s, 18-Me), 1.68-1.75(1H, m, H_(8β)), 1.77-1.86 (1H, m, H_(9β)), 2.10-2.04 (1H, m, H_(9α)),2.54 (1H, d, J=4.9 Hz, H₁₃), 2.56 (1H, d, J=15.7 Hz, H_(14α)), 2.59-2.51(1H, m, H_(8α)), 3.30 (3H, s, OMe), 3.57 (1H, d, J=6.8 Hz, H₂), 3.94(1H, d, J=4.9 Hz, H₁₀), 4.28 and 4.93 (1H, d, J=11.4 Hz, H₁,), 6.07 (1H,broad s, 3-OH), 6.79 (2H, d, J=8.8 Hz, H_(4′)), 7.30 (2H, d, J=8.8 Hz,H_(3′)); ¹³C(C₆D₆, 100 MHz, VR-257) δ 21.9, 22.4, 24.0, 27.4, 35.2,40.0, 44.8, 49.7, 54.8, 61.0, 65.1, 65.4, 72.2, 77.6, 82.6, 91.2, 114.1,129.5, 131.4, 159.7; Anal. Calcd. for C₂₂H₃₀O₅: C, 70.56; H, 8.07;Found: C, 70.65; H, 8.20.

[0105] To a stirred solution of crude material from the preceedingexperiment (7.42 g, 19.8 mmol) in DMF(100 ml) was added at roomtemperature imidazole (6.74 g, 99.0 mmol) then TESCl (10 ml, 59.4 mmol).The reaction was stirred overnight (16 hrs) then was quenched with MeOH(10 ml). The solvents were removed under reduce pressure. To the residuewas added hexanes, then the precipitate formed was filtered throughcelite. The solvent was removed under reduced pressure and the residuewas purified via flash chromatography (9:1 Hex-EtOAc) to afford 9.28 g(93% for two steps) of the epoxide as a colorless oil. 1H (C₆D₆, 500MHz, VR-1-161-2) δ 0.64 (3H, s, 16-Me), 0.70 (6H, q, J=8.0 Hz, TES),0.79 (3H, s, 17-Me), 1.09 (9H, t, J=8.0 Hz, TES), 1.45 (1H, ddd, J=15.5,7.0, 5.0 Hz, H_(14β)), 1.54 (1H, t, J=7.0 Hz, H1), 1.59 (3H, s, 18-Me),1.75-1.81 (1H, m, H_(8β)), 1.86-1.94 (1H, m, H_(9β)), 1.98-2.03 (1H, m,H_(9α)), 2.55 (1H, d, J=5.0 Hz, H₁₃), 2.65 (1H, d, J=15.5 Hz, H_(14α)),2.69-2.76 (1H, m, H_(8α)), 3.32 (3H, s, OMe), 3.64 (1H, d, J=7.0 Hz,H₂), 4.25 (1H, d, J=5.0 Hz, H₁₀), 4.36 and 5.00 (1H, d, J=11.0 Hz,H_(1′)), 5.74 (1H, s, 3-OH), 6.78 (2H, d, J=9.0 Hz, H_(4′)), 7.35 (2H,d, J=9.0 Hz, H_(3′)); 13C(C₆D₆, 100 MHz, VR-1-262) δ 6.0, 7.3, 21.8,22.4, 25.2, 27.9, 36.1, 40.0, 45.7, 49.2, 54.7, 61.6, 65.1, 65.6, 72.1,78.2, 83.9, 91.2, 114.0, 129.6, 131.9, 159.6; Anal. Calcd. forC₂₈H₄₄O₅Si: C, 68.81; H, 9.07; Found: C, 68.58; H, 9.21.

[0106] To a solution of the epoxide from the preceeding experiment (310mg, 634 pmol) in hexanes (6 ml) at room temperature was added titaniumisopropoxide (760 μl, 2.54 mmol, 4 eq.). The reaction mixture wasallowed to stir at reflux for 45 min. After cooling at room temperature,the reaction was quenched with water (2 ml), then EtOAc (10 ml) wasadded. The white precipitate was stirred for 1 hr at room temperature,then was filtered through celite and rinsed with EtOAc. The solution wasconcentrated under reduce pressure to afford 325 mg of crude product asa colorless oil. This oil was generally subjected to the next reactionwithout further purification. A sample from a related experiment waspurified via flash chromatography (8:2 Hex-EtOAc) to afford ketone 17(P₂=PMB, P₁₃=H, P₁₀=TES) as a white solid. Mp 64° C.; ¹H(C₆D₆, 500 MHz,VR-2-130) δ 0.57 (6H, q, J=8.0 Hz, TES), 0.88 (3H, s, 17-Me), 0.98 (9H,t, J=8.0 Hz, TES), 1.04 (3H, s, 16-Me), 1.69 (1H, dddd, J=12.5, 5.0,5.0, 2.5 Hz, H_(9β)), 1.75 (1H, ddd, J=13.0, 5.0, 3.5 Hz, H_(8α)), 1.97(1H, t, J=6.0 Hz, H₁), 2.03 (1H, ddd, J=14.0, 13.0, 2.5 Hz, H_(8β)),2.38 (3H, d, J=1.0 Hz, 18-Me), 2.39 (1H, ddd, J=16.0, 10.0, 6.0 Hz,H_(14β)), 2.66 (1H, dddd, J=14.0, 12.5, 11.0, 3.5 Hz, H_(9α)), 2.74 (1H,dd, J=16.0, 3.0 Hz, H_(14α)), 2.85 (1H, d, J=12.0, 13-OH), 3.27 (3H, s,OMe), 4.05 (1H, m, H₁₃), 4.06 (1H, d, J=6.0 Hz, H₂), 4.32 (1H, dd,J=11.0, 5.0 Hz, H₁₀), 4.06 and 4.39 (1H, d, J=11.5 Hz, H_(1′)), 6.77(2H, d, J=8.5 Hz, H_(4′)), 7.21 (2H, d, J=8.5 Hz, H_(3′)); ¹³C (CDCl₃,100 MHz, VR-1-268) δ 4.8, 6.8, 15.6, 28.1, 28.5, 31.2, 36.4, 36.8, 40.4,51.8, 55.2, 67.1, 69.1, 70.8, 83.5, 113.8, 129.4, 129.8, 138.2, 140.6,159.3, 215.9; Anal. Calcd. for C₂₈H₄₄O₅Si: C, 68.81; H, 9.07; Found: C,68.75; H, 9.14.

[0107] Ketone 17 (P₂=PMB, P₁₃=TBS, P₁₀=TES).

[0108] To a solution of ketone 17 (P₂=PMB, P₁₃=H, P10=TES) (325 mg) inpyridine (6 ml) at −25° C. was added TBSOTf (290 μl, 1.27 mmol, 2 eq.).The mixture was stirred at −20° C. for 4 hrs. The reaction was quenchedby addition of MeOH (1 ml), then the solvents were removed under reducepressure. The white solid was filtered and rinsed with hexanes (8times). The hexane layer was evaporated to afford an oil who waspurified by flash chromatography (9:1 Hex-EtOAc) to afford 377 mg (98%for 2 steps) of ketone 17 (P₂=PMB, P₁₃=TBS, P₁₀=TES) as a colorless oil.¹H (C₆D₆, 500 MHz) δ 0.06 (3H, s, DMS), 0.11 (3H, s, DMS), 0.60 (6H, q,J=8.0 Hz, TES), 1.00 (9H, t, J=8.0 Hz, TES), 1.02 (9H, s, tBu), 1.10(3H, s, 17-Me), 1.18 (3H, s, 16-Me), 1.76 (1H, dddd, J=10.0, 4.4, 4.4,2.4 Hz, H_(9β)), 1.83 (1H, ddd, J=10.4, 4.4, 2.4 Hz, H_(8α)), 2.10-2.14(1H, m, H_(8β)), 2.12-2.16 (1H, m, H₁), 2.24 (3H, d, J=1.0 Hz, 18-Me),2.28 (1H, ddd, J=14.5, 9.0, 9.0 Hz, H_(14β)), 2.65-2.73 (1H, m, H_(9α)),2.69 (1H, ddd, J=14.5, 7.5, 1.5 Hz, H_(14α)), 3.32 (3H, s, OMe), 4.12(1H, d, J=5.0 Hz, H₂), 4.11 and 4.44 (1H, d, J=11.5 Hz, H_(1′)), 4.37(1H, dd, J=11.0, 4.50 Hz, H₁₀), 4.57 (1H, m, H₁₃), 6.79 (2H, d, J=8.5Hz, H_(4′)), 7.23 (2H, d, J=8.5 Hz, H_(3′)); ¹³C (CDCl₃, 100 MHz,VR-1-269) δ −5.0, −4.3, 4.8, 6.8, 15.2, 18.3, 26.0, 28.1, 28.2, 29.2,36.8, 36.9, 40.2, 51.9, 55.2, 67.9, 69.4, 70.3, 83.7, 113.7, 129.5,130.2, 135.0, 143.3, 159.2, 211.2; Anal. Calcd. for C₃₄H₅₈O₅Si₂(VR-1-296): C, 67.72; H, 9.69; Found: C, 67.74; H, 9.61.

[0109] Ketone 18 (P₂=PMB, P₁₃=TBS, P₁₀=TES).

[0110] To a solution of ketone 17 (P₂=PMB, P₁₃=TBS, P₁₀=TES) (200 mg,332 gmol) in dry THF (16.5 ml) at −5° C. was added KHMDS (3.3 ml at 1 Min THF, 3.3 mmol) dropwise over 10 minutes. The pale yellow solution wasstirred at −5° C. for two hours, then was cooled to −78° C. After 30minutes at this temperature, MeI (205 μl, 3.3 mmol) was added dropwiseand the resulting mixture was allowed to stir at −78° C. for 1.5 hours.The reaction was quenched at −78° C. with a saturated NaHCO₃ solution (4ml) then was warmed to room temperature. The mixture was extracted withhexanes. The organic layer was washed with brine then dried over Na₂SO₄.The solvent was removed under reduced pressure. The oil thus obtained(229 mg) was subjected to flash chromatography (9:1 Hex-EtOAc) to afford197 mg (96%) of the ketone 18 (P₂=PMB, P₁₃=TBS, P₁₀=TES) as a whitesolid. Mp. 68° C.; Anal. Calcd. for C₃₅H₆₀O₅Si₂ (VR-2-53): C, 68.13; H,9.80; Found: C, 67.88; H, 9.82. ¹H NMR (C₆D₆, 400 MHz, VR-1-246-1) δ0.08 (3H, s, DMS), 0.15 (3H, s, DMS), 0.60 (6H, q, J=8.0 Hz, TES), 0.83(3H, d, J=7.6 Hz, 19-Me), 0.99 (9H, t, J=8.0 Hz, TES), 1.03 (3H, s,17-Me), 1.09 (9H, s, tBu), 1.15 (3H, s, 16-Me), 1.73 (1H, ddd, J=16.0,3.7, 1.0 Hz, H_(9α)), 1.98 (1H, ddd, J=16.0, 13.2, 5.2 Hz, H_(9β)), 2.12(1H, dd, J=8.0, 2.8 Hz, H₁), 2.35 (3H, d, J=0.8 Hz, 18-Me), 2.35 (1H,ddd, J=14.8, 10.0, 8.0 Hz, H_(14β)), 2.78 (1H, dd, J=14.8, 6.0 Hz,H_(14′)), 2.79-2.87 (1H, m, H_(8α)), 3.29 (3H, s, OMe), 4.00 (1H, d,J=11.2 Hz, H_(1′)), 4.17 (1H, d, J=2.8 Hz, H₂), 4.46 (1H, d, J=11.2 Hz,H_(1′)), 4.57 (1H, broad d, J=5.2 Hz, H₁₀), 4.62 (1H, broad dd, J=10.0,6.0 Hz, H₁₃), 6.79 (2H, d, J=8.8 Hz, H_(4′)), 7.27 (2H, d, J=8.8 Hz,H_(3′)); ¹³C NMR (CDCl₃, 100 MHz, VR-1-265) δ −5.1, -4.3, 4.5, 6.8,14.4, 18.2, 19.2, 25.8, 26.0, 26.8, 29.0, 36.7, 43.1, 43.7, 54.2, 55.2,67.4, 69.6, 69.9, 76.1, 113.7, 129.2, 130.4, 136.6, 138.8, 159.5, 209.6;

[0111] Ketone 19 (P₂=PMB, P₁₃=TBS, P₁₀=TES, P₇=H).

[0112] To a stirred solution of ketone 18 (P₂=PMB, P₁₃=TBS, P₁₀=TES) (49mg, 80 mmol) in THF (2 ml), at room temperature, was added BMDA solution(390 μl at 0.33 M in THF, 127 μmol). The resulting mixture was allowedto stir at room temperature for 2 hrs, then was cooled to −25 C.4-penten-1-al (15 μl, 127 μmol) was added and the reaction mixture wasstirred for 3 hrs, then was treated with NH₄Cl (1 ml). The mixture wasextracted with EtOAc. The organic layer was washed with brine and wasdried over Na₂SO₄. The solution was concentrated under reduce pressureand the crude product was subjected to flash chromatography (9:1Hex-EtOAc) to afford 35 mg (63%) of the ketone 19 (P₂=PMB, P₁₃=TBS,P₁₀=TES, P₇=H) as a colorless oil (mixture of 2 conformers: 85%chair-chair and 15% chair-boat). ¹H NMR (C₆D₆, 400 MHz) δ 0.07 (3H, s,DMS), 0.14 (3H, s, DMS), 0.61 (6H, q, J=8.0 Hz, TES), 1.00 (9H, t, J=8.0Hz, TES), 1.02 (3H, s, 19-Me), 1.06 (3H, s, 17-Me), 1.07 (9H, s, tBu),1.26 (3H, s, 16-Me), 1.40-1.49 (1H, m, H₆), 1.61-1.68 (1H, m, H₆), 1.93(1H, dd, J=14.0, 4.8 Hz, H_(9β)), 2.10 (1H, dd, J=8.8, 3.6 Hz, H₁),2.21-2.28 (1H, m, H₅), 2.28 (3H, d, J=1.2 Hz, 18-Me), 2.27-2.35 (1H, m,H_(14β)), 2.41-2.50 (1H, m, H₅), 2.76 (1H, dd, J=14.0, 6.2 Hz, H_(9α)),2.92 (1H, dd, J=14.6, 6.2 Hz, H_(14α)), 3.06 (1H, d, J=2, 8 Hz, 7-OH),3.29 (3H, s, OMe), 3.96 (1H, ddd, J=10.0, 4.0, 1.6 Hz, H₇), 4.16 (1H, d,J=11.6 Hz, H_(1′)), 4.33 (1H, d, J=11.6 Hz, H_(1′)), 4.38 (1H, d, J=3.6Hz, H₂), 4.53-4.58 (2H, m, H₁₃ and H₁₀), 4.98-5.01 (1H, m, H_(20b)),5.11 (1H, ddd, J=17.2, 3.8, 1.4 Hz, H_(20c)), 5.92 (1H, ddt, J=17.2,10.4, 6.8 Hz, H_(4a)), 6.80 (2H, d, J=8.8 Hz, H_(4′)), 7.22 (2H, d,J=8.8 Hz, H_(3′)).

[0113] Ketone 19 (P₂=PMB, P₁₃=TBS, P₁₀=TES, P₇=CO₂Et).

[0114] To a stirred solution of ketone 19 (P₂=PMB, P₁₃=TBS, P₁₀=TES,P₇=H) (23 mg, 33 μmol) in CH₂Cl₂ (3 ml) and pyridine (240 μl, 3.0 mmol)at −40° C., was added a solution of phosgene (˜50 μl at 5.5 M inCH₂Cl₂). The resulting mixture was allowed to stir at −10° C. for 1.5hr, then EtOH (300 μl) was added. The reaction mixture was stirred atroom temperature for 1 hr, then was treated with NaHCO₃ (2 ml). Themixture was extracted with EtOAc. The organic layer was washed withbrine, was dried over Na₂SO₄ then was concentrated under reducepressure. The crude product was subjected to flash chromatography (9:1Hex-EtOAc) to afford 25 mg (99%) of ketone 19 (P₂=PMB, P₁₃=TBS, P₁₀=TES,P₇=CO₂Et) as a white solid. Mp. 121° C.; ¹H(C₆D₆, 400 MHz, VR-2-73-2) δ0.03 (3H, s, DMS), 0.12 (3H, s, DMS), 0.62 (6H, q, J=8.0 Hz, TES), 0.99(9H, t, J=8.0 Hz, TES), 1.01 (9H, s, tBu), 1.01 (3H, t, J=7.2 Hz,CO₂Et-CH₃), 1.12 (3H, s, 17-Me), 1.19 (3H, s, 19-Me), 1.29 (3H, s,16-Me), 1.50-1.56 (2H, m, H₆), 1.97 (1H, dd, J=11.4, 4.6 Hz, H_(9β)),2.10 (1H, dd, J=8.4, 3.6 Hz, H₁), 2.13-2.19 (2H, m, H₅), 2.24 (3H, d,J=1.2 Hz, 18-Me), 2.27-2.35 (1H, ddd, J=14.8, 9.4, 9.4 Hz, H_(14β)),2.95 (1H, t, J=11.4 Hz, H_(9α)), 2.96 (1H, dd, J=14.8, 6.4 Hz, H_(14α)),3.29 (3H, s, OMe), 3.95 (2H, dq, J=18.0, 7.2 Hz, CO₂Et-CH₂), 4.29 (2H,s, H_(1′)), 4.39 (1H, d, J=3.6 Hz, H₂), 4.55 (1H, dd, J=11.4, 4.6 Hz,H₁₀), 4.58-4.63 (1H, m, H₁₃), 4.86-4.89 (1H, m, H₂Ob), 4.94 (1H, ddd,J=17.2, 3.4, 1.6 Hz, H_(20c)), 5.69 (1H, dddd, J=17.2, 10.4, 6.8, 6.8Hz, H_(4a)), 5.76 (1H, t, J=6.2 Hz, H₇), 6.80 (2H, d, J=8.8 Hz, H_(4′)),7.20 (2H, d, J=8.8 Hz, H_(3′)); 13C (CDCl₃, 100 MHz, VR-2-76) δ −5.0,−4.1, 5.0, 6.8, 14.2, 14.8, 16.2, 18.3, 26.1, 28.1, 28.2, 29.7, 30.6,37.1, 47.5, 50.6, 54.7, 55.3, 63.9, 66.3, 68.3, 70.1, 74.9, 84.1, 113.9,114.7, 128.8, 129.8, 130.3, 134.1, 137.9, 145.1, 155.3, 159.5, 212.3.

[0115] Ketone 19 (P₂=H, P₁₃=TBS, P₁₀=TES, P₇=CO₂Et).

[0116] To a stirred suspension of ketone 19 (P₂=PMB, P₁₃=TBS, P₁₀=TES,P₇=CO₂Et) (13.7 mg, 18 μmol) in CH₂Cl₂ (1.8 ml) and water (180 μl) at 0°C., was added DDQ(12 mg, 53 μmol, 3 eq.). The resulting mixture wasallowed to stir at −10° C. for 1.5 hr, then EtOH (300 μl) was added. Thereaction mixture was stirred at room temperature for 5 hrs, then wastreated with Na₂S₂O₃ solution (1 ml) and NaHCO₃ solution (1 ml). Themixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ then was concentrated under reduce pressure.The crude product was subjected to flash chromatography (95:5 Hex-EtOAc)to afford 10 mg (83%) of ketone 19 (P₂=H, P₁₃=TBS, P₁₀=TES, P₇=CO₂Et) asa colorless oil. ¹H (CDCl₃, 500 MHz, VR-2-166-3) δ 0.07 (3H, s, DMS),0.08 (3H, s, DMS), 0.56 (6H, q, J=8.0 Hz, TES-CH₂), 0.92 (9H, t, J=8.0Hz, TES-CH₃), 0.96 (9H, s, tBu), 1.09 (3H, s, 17-Me), 1.14-1.20 (1H, m,H₆), 1.31 (3H, t, J=7.0 Hz, CO₂Et-CH₃), 1.40 (3H, s, 19-Me), 1.42-1.49(1H, m, H₆), 1.55 (3H, s, 16-Me), 1.71 (1H, dd, J=12.5, 4.5 Hz, H_(9β)),1.83 (3H, d, J=0.5 Hz, 18-Me), 1.89 (1H, dd, J=14.9, 6.0 Hz, H_(14α)),2.03 (1H, dd, J=8.8, 4.3 Hz, H₁), 1.99-2.12 (2H, m, H₅), 2.21 (1H, ddd,J=14.9, 8.8, 8.7 Hz, H_(14β)), 2.50 (1H, dd, J=12.5, 11.5 Hz, H_(9α)),2.80 (d, 1H, J=10.5 Hz, 2-OH), 4.20 (2H, dq, J=7.0, 2.0 Hz, CO₂Et-CH₂),4.40 (1H, broad dd, J=8.8, 6.0 Hz, H₁₃), 4.47 (1H, dd, J=11.5, 4.5 Hz,H₁₀), 4.55 (1H, dd, J=10.5, 4.3 Hz, H₂), 4.92 (1H, dd, J=10.0, 1.8 Hz,H₂₀), 4.98 (1H, dd, J=17.0, 1.8 Hz, H₂₀), 5.28 (1H, d, J=8.5 Hz, H₇),5.73 (1H, dddd, J=17.0, 10.0, 6.5, 6.5 Hz, H_(4a)); 13C (CDCl₃, 125 MHz,VR-2-166-3) δ −5.0, −4.2, 4.9, 6.8, 14.2, 15.2, 16.2, 18.2, 26.0, 27.7,28.0, 28.3, 30.6, 37.0, 47.3, 54.6, 54.8, 64.0, 66.2, 67.8, 70.3, 83.6,114.8, 135.2, 137.7, 144.3, 155.3, 217.3.

[0117] Ketone 20 (P₂=PMB).

[0118] To a solution of 1.5 g (4.23 mmol) of 15 (P₂=PMB, P₁₀=H) in 10 mlof DMF at 0° C. was slowly added 2.07 g (5.55 mmol) of PDC (in threeportions). The temperature was then allowed to rise at room temperature.After 2 h, the mixture was poured into 10 ml of water and extracted with3×50 ml of ethyl acetate. The combined organic layers were dried overNa₂SO₄ and concentrated. Flash chromatography (hexane/ethyl acetate 7:3)gave 1.48 g (99%) of the ketone 20 (P₂=PMB) as a pale yellow solid. ¹HNMR (500 MHz, CDCl₃), δ (ppm): 1.05 (s, 3H, 16Me), 1.16 (s, 3H, 17Me),1.61 (dt, J=2.3, 1.7, 1.7 Hz, 3H, 18Me), 2.04 (ddq, J=17.5, 2.8, 2.3 Hz,1H, H14β), 2.06 (m, 1H, H₁), 2.09 (dddd, J=13.6, 11.3, 9, 2 Hz, 1H,H8β), 2.37 (ddd, J=13.6, 10.7, 1.7 Hz, 1H, H8α), 2.42 (ddd, J=19.2, 9,1.7 Hz, 1H, H9β), 2.46 (ddq, J=17.5, 3.4, 1.7 Hz, 1H, H14α), 2.67 (ddd,J=19.2, 11.3, 10.7 Hz, 1H, H9α), 3.14 (d, J=2 Hz, 1H, 3-OH), 3.81 (s,3H, OMe), 4.00 (d, J=6.2 Hz, 1H, H2β), 4.42 (d, J=10.7 Hz, 1H, Hb), 4.65(d, J=10.7 Hz, 1H, Ha), 5.40 (m, J=1.7 Hz, 1H, H13), 6.89 (d, J=8.5 Hz,2H, H2′), 7.28 (d, J=8.5 Hz, 2H, H1′); ¹³C NMR (100 MHz, CDCl₃), δ(ppm): 21.7, 22.0, 25.1, 25.4, 37.2, 41.1, 41.2, 49.1, 55.2, 69.9, 72.5,83.9, 88.4, 113.8, 121.6, 129.3, 130.2, 136.5, 159.3, 218.6.

[0119] Alkene 22 (P₂=PMB, P₁₀=TES).

[0120] To a mixture of 170 mg (0.47 mmol) of the above ketone 20(P₂=PMB) in 3.8 ml of ether at 0° C. was slowly added 955 μl (0.95 mmol)of a 1M solution of LAH in ether. After2 h, 1 ml of water, 1 ml of a 1Maqueous solution of NaOH and 2 ml of water were added successively andthe mixture was stirred for 3 h at room temperature then filtered oncelite, dried over Na₂SO₄ and concentrated. Flash chromatography(hexane/ethyl acetate 7:3) afforded 155 mg (91%) of 10-βhydroxycompound. ¹H NMR (500 MHz, CDCl₃), δ (ppm): 1.25 (s, 3H, 17Me), 1.31 (s,3H, 16Me), 1.81 (m, J=2.2, 1.5 Hz, 3H, 18Me), 1.85 (dd, J=5.9, 5.5 Hz,1H, H₁), 1.97 (m, 1H, H9β), 2.00 (m, J=10.3, 1.8 Hz, 1H, H8β), 2.00 (m,J=18 Hz, 1H, H14β), 2.13 (m, 1H, H8α), 2.26 (dd, J=9.4, 2.2 Hz, 1H,H9α), 2.36 (dq, J=8, 1.8 Hz, 1H, H14α), 3.00 (br, 1H, 3-OH), 3.81 (s,3H, OMe), 3.90 (d, J=5.9 Hz, 1H, H2β), 4.33 (d, J=11.4 Hz, 1H, Hb), 4.57(d, J=11.4 Hz, 1H, Ha), 4.84 (dd, J=9.4, 8.4 Hz, 1H, H10α), 5.44 (m,J=1.5 Hz, 1H, H13), 6.87 (d, J=8.8 Hz, 2H, H2′), 7.26 (d, J=8.8 Hz, 2H,H1′).

[0121] To a mixture of 98 mg (0.27 mmol) of the above diol in 93 mg(1.36 mmol) of imidazole and 2.7 ml of DMF was added 92 μl (0.55 mmol)of TESCl, hie resulting mixture was stirrred at room temperature for 14h. After addition of 3 ml of methanol, the mixture was concentrated,diluted with 10 ml of hexane and filtered. The organic layer wasconcentrated to give after flash chromatography (hexane:ethyl acetate9:1) 126 mg (98%) of pure 10-β-protected alkene 22 (P₂=PMB, P₁₀=TES) asa colorless oil. ¹H NMR (500 MHz, CDCl₃), δ (ppm): 0.59 (q, J=8 Hz, 6H,CH₂ 10-TES), 0.95 (t, J=8 Hz, 9H, CH₃ 10-TES), 1.20 (s, 3H, 17Me), 1.25(s, 3H, 16Me), 1.77 (td, J=2.2, 2.2, 1.6 Hz, 3H, 18Me), 1.81 (dd, J=6.1,5.8 Hz, 1H, H1), 1.90 (m, 1H, H9β), 1.97 (m, J=18.2 Hz, 1H, H14β), 2.00(m, 1H, H8β), 2.08 (ddd, J=14.1, 7.4, 1 Hz, 1H, H8α), 2.15 (ddd, J=14.1,9.3, 3.5 Hz, 1H, H9α), 2.32 (dd, J=18.2, 3.2 Hz, 1H, H14α), 2.94 (d,J=1.3 Hz, 1H, 3-OH), 3.78 (s, 3H, OMe), 3.86 (d, J=6.1 Hz, 1H, H2β),4.31 (d, J=11.2 Hz, 1H, Hb), 4.55 (d, J=11.2 Hz, 1H, Ha), 4.79 (dd,J=9.3, 9 Hz, 1H, H10α), 5.37 (ddq, J=3.5, 3.2, 1.6 Hz, 1H, H13), 6.85(d, J=8.6 Hz, 2H, H2′), 7.24 (d, J=8.6 Hz, 2H, H1′); ¹³C NMR (100 MHz,CDCl₃), δ (ppm): 5.2, 6.9, 22.8, 23.2, 25.6, 27.0, 34.0, 40.2, 40.3,51.0, 55.2, 65.7, 67.9, 72.1, 85.8, 88.7, 113.7, 122.1, 129.1, 130.7,139.9, 159.1.

[0122] Ketone 24 (P₂=PMB, P10=TES, P₁₃=H).

[0123] To a mixture of 70 mg (0.15 mmol) of the above alcohol 22(P₂=PMB, P₁₀=TES) in 686 μl of dichloromethane was added 177 μl (0.6mmol) of Ti(OiPr)₄, the resulting solution was stirred for 15 min atroom temperature and 77 μl (0.752 mmol) of tBuOOH was introduced. After1 h 30 at room temperature, 500 μl (excess) of dimethylsulfide was addedand the mixture was refluxed for 14 h. The solvents were removed underreduced pressure and the residue was dissolved in 5 ml of ethyl acetateand 300 μl of water. After stirring for 3 h at room temperature, themixture was dried over Na₂SO₄, filtered through a cake of celite andconcentrated. A plug chromatography (hexane/ethyl acetate 7:3) led to77.8 mg (100%) of ketone 24 (P₂=PMB, P₁₀=TES, P1 ₃=H) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.58 (q, J=8.1 Hz, 6H, CH₂10-TES), 0.95 (t, J=8.1 Hz, 3H, CH₃ 10-TES), 0.99 (s, 3H, 17Me), 1.59(s, 3H, 16Me), 1.67 (d, J=1.8 Hz, 3H, 18Me), 1.85 (ddd, J=13.9, 6, 3.3Hz, 1H, H9α), 1.94 (m, J=6.6, 2.6 Hz, 1H, H8α), 2.04 (dd, J=7.3, 3.3 Hz,1H, H1), 2.20 (ddd, J=14.3, 7.7, 3.3 Hz, 1H, H8β), 2.21 (dd, J=15.8, 3.3Hz, 1H, H14α), 2.29 (m, 1H, H9β), 2.62 (ddd, J=15.8, 10.5, 7.3 Hz, 1H,H14β), 3.80 (s, 3H, OMe), 4.07 (dd, J=10.5, 1.8 Hz, 1H, H13β), 4.25 (d,J=11.4 Hz, 1H, Hb), 4.37 (d, J=3.3 Hz, 1H, H2β), 4.37 (d, J=11.4 Hz, 1H,Ha), 4.75 (dd, J=10.3, 6 Hz, 1H, H10α), 6.86 (d, J=8.8 Hz, 2H, H2′),7.22 (d, J=8.8 Hz, 2H, H1′).

[0124] Ketone 24 (P₂=PMB, P₁₀=TES, P₁₃=TBS).

[0125] To a solution of 143 mg (0.3 mmol) of crude ketone 24 (P₂=PMB,P₁₀=TES, P₁₃=H) in 2 ml of pyridine at −25° C. was slowly added 134 μl(0.6 mmol) of TBSOTf. The mixture was then stirred at −10° C. for 3 h,dilute by 20 ml of hexane, quenched by addition of 1 ml of methanol andconcentrated. The residue was dissolved in 20 ml of hexane and washed by3 ml of a saturated aqueous solution of NaHCO₃. The aqueous layer wasextracted by 10 ml of dichloromethane and 10 ml of ethyl acetate. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Flashchromatography (hexane/ethyl acetate 9:1) afforded 178.3 mg (100%) ofketone 24 (P₂=PMB, P¹⁰=TES, P₁₃=TBS). ¹H NMR (400 MHz, CDCl₃), δ (ppm):0.05 (s, 3H, CH₃ 13-TBS), 0.09 (s, 3H, CH₃ 13-TBS), 0.57 (q, J=7.8 Hz,6H, CH₂ 10-TES), 0.95 (t, J=7.8 Hz, 9H, CH₃ 10-TES), 0.96 (s, 9H, (CH₃)₃13-TBS), 1.04 (s, 3H, 17Me), 1.59 (s, 3H, 16Me), 1.60 (d, J=1.1 Hz, 3H,18Me), 1.83 (ddd, J=13.7, 6.6, 3.4 Hz, 1H, H9α), 1.94 (m, J=15.8 Hz, 1H,H14β), 1.98 (dd, J=7.4, 3 Hz, 1H, H1), 2.16 (dd, J=14, 3.4 Hz, 1H, H8β),2.22 (m, 1H, H8α), 2.25 (dd, J=15.8, 3.8 Hz, 1H, H14α), 2.27 (m, J=7 Hz,1H, H9β), 3.80 (s, 3H, OMe), 4.17 (d, J=11.5 Hz, 1H, Hb), 4.33 (d, J=3Hz, 1H, H₂O, 4.38 (d, J=11.5 Hz, 1H, Ha), 4.42 (m, J=9.1, 1.1 Hz, 1H,H13β), 4.77 (dd, J=10.8, 6.6 Hz, 1H, H10α), 6.84 (d, J=8.6 Hz, 2H, H2′),7.23 (d, J=8.6 Hz, 2H, H1′).

[0126] Ketone 26 (P2=PMB, P9=H).

[0127] To a cooled solution of ketone 20 (866 mg, 2.4 mmol) in 24 ml ofTHF and 1.7 ml (9.73 mmol) of HMPA at −10° C. was added 9.73 ml (9.73mmol) of a 1M solution of LiHMDS in THF The mixture was stirred for 1 hthen cooled to −78° C. and 1 ml (6.08 mmol) of a solution of TESCl wasadded. The resulting mixture was stirred for 1 h at −78° C. and pouredinto 100 ml of hexane. The organic layer was then washed by 20 ml of asaturated aqueous solution of NaHCO₃ followed by 20 ml of brine. Thecombined aqueous layers were extracted by 50 ml of hexane. The organiclayer was dried over Na₂SO₄ and concentrated to give 1.87 g of crudecompound as a yellow oil (3,10 bis TES enol-ether). ¹H NMR (500 MHz,CDCl₃), δ (ppm): 0.46 (q, J=7.6 Hz, 6H, CH₂ TES), 0.72 (q, J=7.6 Hz, 6H,CH₂ TES), 0.83 (t, J=7.6 Hz, 9H, CH₃ TES), 0.94 (s, 3H, 16Me), 1.00 (t,J=7.6 Hz, 9H, CH₃ TES), 1.17 (s, 3H, 17Me), 1.67 (m, J=1.6, 1.8 Hz, 3H,18Me), 1.96 (m, 2H, H14β-H1), 2.28 (m, J=16.7, 1.8 Hz, 1H, H14α), 2.30(dd, J=16, 2.1 Hz, 1H, H8), 2.41 (dd, J=16, 2.5 Hz, 1H, H8), 3.81 (s,3H, OMe), 3.82 (dd, J=5.2, 0.9 Hz, 1H, H2β), 4.26 (d, J=10.8 Hz, 1H,Hb), 4.38 (d, J=10.8 Hz, 1H, Ha), 4.45 (dd, J=2.5, 2.1 Hz, 1H, H9), 5.17(m, 1H, H13), 6.86 (d, J=8.7 Hz, 2H, H2′), 7.27 (d, J=8.7 Hz, 2H, H1′).

[0128] To a mixture of crude (1.87 g) and 613 mg (7.3 mmol) of NaHCO₃ in50 ml of hexane was added at 0° C. 900 mg (3.6 mmol) of mCPBA. Themixture was stirred at 0° C. for 4 h and diluted by 100 ml of hexane.The organic layer was washed twice with 50 ml of a saturated solution ofNaHCO₃/Na₂S₂O₃ (1:1), dried over Na₂SO₄ and concentrated.

[0129] To a solution of the above crude in 10 ml of THF at 0° C. wasadded 12 ml (12 mmol) of a 1M solution of TBAF in THF The resultingsolution was stirred for 1 h at room temperature. The mixture wasdiluted with 100 ml of ethyl acetate, washed with 20 ml of a saturatedaqueous solution of NaHCO₃, 20 ml of brine, dried over Na₂SO₄ andconcentrated. A flash chromatography (hexane/ethyl acetate 1:1) led to690 mg (76% over 3 steps) of ketone 26 (P₂=PMB, Pg=H). ¹H NMR (300 MHz,CDCl₃), δ (ppm): 0.99 (s, 3H, 16Me), 1.16 (s, 3H, 17Me), 1.69 (m, J=1.8Hz, 3H, 18Me), 2.07 (m, J=2.3 Hz, 1H, H145), 2.09 (m, 1H, H1), 2.33 (dd,J=15.8, 1.8 Hz, 1H, H8α), 2.44 (ddd, J=15.8, 7, 1.8 Hz, 1H, H8β), 2.48(m, 1H, H14α), 2.91 (br, 1H, 9-OH), 2.35 (br, 1H, 3-OH), 3.81 (s, 3H,OMe), 4.01 (d, J=5.9 Hz, 1H, H2′), 4.02 (m, 1H, H9β), 4.42 (d, J=11.2Hz, 1H, Hb), 4.64 (d, J=11.2 Hz, 1H, Ha), 5.45 (m, 1H, H13), 6.90 (d,J=8.3 Hz, 2H, H2′), 7.29 (d, J=8.3 Hz, 2H, H1′).

[0130] Ketone 26 (P₂=PMB, P₉=TES).

[0131] To a solution of 718 mg (1.26 mmol) of crude above ketone 26(P₂=PMB, P₉=H) in 13.5 ml of dichloromethane and 2 ml (14.13 mmol) oftriethylamine at 0° C. was slowly added a catalytic amount of DMAP and710 μl (4.2 mmol) of TESCl. The mixture was stirred under nitrogen for 1h. After addition of 3 ml of methanol, the resulting mixture was stirredfor 15 min at room temperature and concentrated. The crude was dissolvedin 100 ml of hexane and the salts were filtered. The organic layer wasthen dried over Na₂SO₄ and concentrated to give after flashchromatography (hexane/ethyl acetate 8:2) 604 mg (88% over 2 steps) ofketone 26 (P₂=PMB, P₉=TES) as a colorless oil. ¹H NMR (500 MHz, CDCl₃),δ (ppm): 0.60 (q, J=8 Hz, 6H, CH₂ 9-TES), 0.95 (s, 3H, 16Me), 0.98 (t,J=8 Hz, 9H, CH₃ 9-TES), 1.30 (s, 3H, 17Me), 1.67 (td, J=2.2, 2.2, 1.3Hz, 3H, 18Me), 2.20 (m, J=6.1 Hz, 1H, H1), 2.22 (ddq, J=14.2, 3.2, 2.2Hz, 1H, H14β), 2.31 (dd, J=15.3, 2.2 Hz, 1H, H8α), 2.42 (ddd, J=15.3,7.7, 1.3 Hz, 1H, H8β), 2.47 (ddq, J=14.2, 3.5, 2.2 Hz, 1H, H14α), 3.10(br, 1H, 3-OH), 3.80 (s, 3H, OMe), 3.95 (d, J=6.1 Hz, 1H, H2β), 4.05(dd, J=7.7, 2.2 Hz, 1H, H9β), 4.37 (d, J=11.2 Hz, 1H, Hb), 4.67 (d,J=11.2 Hz, 1H, Ha), 5.40 (ddq, J=3.5, 3.2, 1.3 Hz, 1H, H13), 6.86 (d,J=8.6 Hz, 2H, H2′), 7.28 (d, J=8.6 Hz, 2H, H1′).

[0132] Triol 27 (P₂=PMB, P₉=P₁₀=H).

[0133] To a mixture of 590 mg (1.58 mmol) of 3,9-dihydroxyketone 26 in20 ml of ether at 0° C. was slowly added 2.4 ml (2.4 mmol) of a 1Msolution of lithiumaluminiumhydride in ether. After 2 h, the reactionwas quenched by addition of 3 ml of water, 3 ml of a 1 M solution ofNaOH and 6 ml of water. The resulting solution was stirred for 2 h atroom temperature and diluted with 100 ml of ethyl acetate. Afterfiltration through a cake of celite the organic layer was dried overNa₂SO₄ and concentrated to give 530 mg (90%) of triol 27 as a colorlessoil.

[0134] Alkene 27 (P₂=PMB, P₉=TES, P₁₀=H).

[0135] To a solution of 530 mg (1.41 mmol) of the above triol 27(P₂=PMB, P₉=P₁₀=H) in 26 ml of dichloromethane and 2 ml (14.13 mmol) oftriethylamine at 0° C. was slowly added a catalytic amount of DMAP and355 μl (2.11 mmol) of TESCl. The mixture was stirred under nitrogen for1 h. After addition of 5 ml of methanol, the resulting mixture wasstirred for 15 min at room temperature then concentrated. The crude wasdissolved in 150 ml of hexane and filtered. The organic layer wasconcentrated to give after flash chromatography (hexane/ethyl acetate8:2) 649 mg (94%) of diol 27 (P₂=PMB, P₉=TES, P₁₀=H) as white solid.m.p. 90-92° C.; ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.59 (q, J=8.1 Hz, 6H,CH₂ 9-TES), 0.96 (t, J=8.1 Hz, 9H, CH₃ 9-TES), 1.15 (s, 3H, 16Me), 1.21(s, 3H, 17Me), 1.59 (br s, 1H, 10-OH), 1.78 (t, J=5.7 Hz, 1H, H1), 1.81(dt, J=2.4, 1.9, 1.9 Hz, 3H, 18Me), 1.97 (ddq, J=18.2, 3.4, 2.4 Hz, 1H,H14β), 1.99 (dd, J=14.8, 6.3 Hz, 1H, H8α), 2.28 (dd, J=14.8, 9.1 Hz, 1H,H8β), 2.32 (ddq, J=18.2, 3.4, 1.9 Hz, 1H, H14α), 3.00 (br s, 1H, 3-OH),3.79 (s, 3H, OMe), 3.81 (d, J=5.7 Hz, 1H, H2β), 4.29 (d, J=11 Hz, 1H,Hb), 4.40 (ddd, J=9.1, 7.7, 6.3 Hz, 1H, H9β), 4.45 (t, J=7.7 Hz, 1H,H10α), 4.54 (d, J=11Hz, 1H, Ha), 5.40 (m, J=3.4 Hz, 1H, H13), 6.85 (d,J=8.6 Hz, 2H, H2′), 7.26 (d, J=8.6 Hz, 2H, H1′).

[0136] Ketone 28 (P₂=PMB, P₉=TES, P₁₀=H, P₁₃=H). To a solution of 400 mg(0.83 mmol) of the above diol 27 (P2=PMB, P₉=TES, P₁₀=H) in 5 ml ofdichloromethane at 0° C. was added 987 μl (3.31 mmol) of Ti(OiPr)₄,after 30 min, 425 μl (4.15 mmol) of tBuOOH was added. The resultingmixture was stirred for 4 h at 0° C. and 1.24 ml (16.6 mmol) ofdimethylsulfide was introduceded and the resulting mixture was stirredat room temperature for 14 h. The mixture was concentrated and the cruderesidue was dissolved in 200 ml of THF. 3 ml of water was added andafter 3 h, the mixture was dried over Na₂SO₄, filtered and concentratedto give 496.4 mg of crude compound 28 (P₂=PMB, P₉=TES, P₁₀=H, P₁₃=H) asa colorless oil.

[0137] Ketone 28 (P₂=PMB, P₉=TES, P₁₀=H, P₁₃=TBS).

[0138] To a solution of 496.4 mg of crude ketone 28 (P₂=PMB, P₉=TES,P₁₀=H, P₁₃=H) in 3.3 ml of pyridine at −45° C. was added 420 μl (1.82mmol) of TBSOTf. The reaction was stirred at −10° C. for 2 h, dilutedwith 20 ml of hexane, quenched by addition of 500 μl of methanol andstirred for 30 min. The volatils were concentrated and the residue wasdissolved in 20 ml of hexane and filtered. The organic layer wasconcentrated to lead after flash chromatography (hexane/ethyl acetate9:1) to 450 mg (89% over 2 steps) of pure ketone 28 (P₂=PMB, P₉=TES,P₁₀=H, P₁₃=TBS) as a pale yellow solid. m.p. 64-66° C.; ¹H NMR (500 MHz,CDCl₃), 3 (ppm): δ (s, 3H, CH₃ 13-TBS), 0.10 (s, 3H, CH₃ 13-TBS), 0.58(q, J=7.9 Hz, 6H, CH₂ 9-TES), 0.95 (t, J=7.9 Hz, 9H, CH₃ 9-TES), 0.96(s, 9H, (CH₃)₃ 13-TBS), 1.10 (s, 3H, 17Me), 1.52 (s, 3H, 16Me), 1.70 (d,J=1.1 Hz, 3H, 18Me), 1.98 (dd, J=7.3, 2.9 Hz, 1H, H1), 2.04 (dd, J=16.9,4.4 Hz, 1H, H8,), 2.07 (d, J=2.3 Hz, 1H, 10-OH), 2.26 (dd, J=14.9, 5.7Hz, 1H, H14α), 2.30 (dd, J=14.9, 7.3 Hz, 1H, H14β), 2.35 (dd, J=16.9, 12Hz, 1H, H8α), 3.80 (s, 3H, OMe), 4.16 (d, J=2.9 Hz, 1H, H2β), 4.24 (d,J=12 Hz, 1H, Hb), 4.39 (ddd, J=12, 8.8, 4.4 Hz, 1H, H9β), 4.44 (d, J=12Hz, 1H, Ha), 4.46 (m, 1H, H13β), 4.55 (dd, J=8.8, 2.3 Hz, 1H, H10α),6.86 (d, J=8.6 Hz, 2H, H2′), 7.22 (d, J=8.6 Hz, 2H, H1′); ¹³C NMR(100MHz, CDCl₃), δ (ppm): −5.1, −4.2, 4.9, 6.7, 15.9, 18.1, 21.4, 22.3,25.4, 25.7, 41.1, 48.4, 48.9, 55.2, 69.9, 72.4, 76.5, 84.6, 86.9, 113.7,121.1, 128.3, 130.2, 136.8, 159.2, 216.2.

[0139] Ketone 28 (P₂=PMB, P₉=TMS, P₁₀=TES, P₁₃=TBS).

[0140] To a solution of 218 mg (0.35 mmol) of ketone 28 (P₂=PMB, P₉=TES,P₁₀=H, P₁₃=TBS) in 6.4 ml THF at −78° C. was added 92 μl (0.53 mmol)HMPA and 530 μl (0.53 mmol) of a 1M solution of LiHMDS in THE Themixture was stirred at −20° C. for 1 h and cooled to 78° C. 148 μl (1.06mmol) of triethylamine and 90 μl (0.7 mmol) of TMSCl were successivelyadded. After 30 min, the mixture was diluted with 20 ml of hexane,washed by 10 ml of a 1:1 aqueous solution of NaHCO₃ and brine. Theaqueous layer was extracted by 20 ml of a solution of hexane/ethylacetate (8:2), the combined organic layers were dried over Na₂SO₄ andconcentrated. After flash chromatography (hexane/ethyl acetate 9:1), 207mg (93%) of ketone 28 (P₂=PMB, P₉=TMS, P₁₀=TES, P₁₃=TBS) was obtained asa colorless oil.

[0141]¹H NMR (400 MHz, C₆D₆), δ (ppm): 0.04 (s, 3H, CH₃ 13-TBS), 0.13(s, 9H, CH₃ 9-TMS), 0.14 (s, 3H, CH₃ 13-TBS), 0.68 (q, J=8.1 Hz, 6H, CH₂10-TES), 1.04 (t, J=8.1 Hz, 9H, CH₃ 10-TES), 1.08 (s, 9H, (CH₃)₃13-TBS), 1.10 (s, 3H, 17Me), 1.64 (s, 3H, 16Me), 1.89 (s, 3H, 18Me),2.08 (dd, J=8.1, 2.9 Hz, 1H, H1), 2.15 (dd, J=16.9, 4.4 Hz, 1H, H8),2.40 (ddd, J=14.7, 10.3, 8.1 Hz, 1H, H14β), 2.63 (dd, J=16.9, 11.7 Hz,1H, H8α), 2.75 (dd, J=14.7, 5.5 Hz, 1H, H14α), 3.29 (s, 3H, OMe), 4.18(d, J=11.7 Hz, 1H, Hb), 4.30 (d, J=2.9 Hz, 1H, H2β), 4.48 (ddd, J=11.7,8.4, 4.4 Hz, 1H, H9β), 4.49 (d, J=11.7 Hz, 1H, Ha), 4.55 (dd, J=10.3,5.5 Hz, 1H, H13β), 4.75 (d, J=8.4 Hz, 1H, H10α), 6.76 (d, J=8.4 Hz, 2H,H2′), 7.18 (d, J=8.6 Hz, 2H, H1′).

[0142] Ketone 29 (P₂=PMB, P₉=TMS, P₁₀=TES, P₁₃=TBS).

[0143] To a solution of 103 mg (0.15 mmol) of ketone 28 (P₂=PMB, P₉=TMS,P₁₀=TES, P₁₃=TBS) in 5 ml of THF and 94 μl (1.5 mmol) of methyliodide at−78° C. was slowly added 3 ml (1.5 mmol) of a 0.5M solution of KHMDS inTHF The reaction mixture was stirred for 4 h at −78° C. and diluted byaddition of 50 ml of hexane and extracted by 10 ml of a saturatedaqueous solution of NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated to afford 105.4 mg(100%) of β19-methyl ketone 29 (P₂=PMB,P₉=TMS, P₁₀=TES, P₁₃=TBS) as a colorless oil. ¹H NMR (500 MHz, C₆D₆), δ(ppm): 0.04 (s, 3H, CH₃ 13-TBS), 0.14 (s, 3H, CH₃ 13-TBS), 0.22 (s, 9H,CH₃ 9-TMS), 0.75 (q, J=8.1 Hz, 6H, CH₂ 10-TES), 1.04 (t, J=8.1 Hz, 9H,CH₃ 10-TES), 1.07 (d, J=7.4 Hz, 3H, 19Me), 1.09 (s, 9H, (CH₃)₃ 13-TBS),1.11 (s, 3H, 17Me), 1.65 (s, 3H, 16Me), 1.88 (s, 3H, 18Me), 2.12 (dd,J=8.1, 3.1 Hz, 1H, H1), 2.36 (ddd, J=14.2, 10.1, 8.1 Hz, 1H, H14β), 2.45(dd, J=10.9, 7.4 Hz, 1H, H8α), 2.79 (dd, J=14.2, 5.5 Hz, 1H, H14α), 3.28(s, 3H, OMe), 4.07 (d, J=11.1 Hz, 1H, Hb), 4.24 (dd, J=10.9, 8.1 Hz, 1H,H9β), 4.28 (d, J=3.1 Hz, 1H, H2β), 4.45 (d, J=11.1 Hz, 1H, Ha), 4.54(dd, J=10.1, 5 Hz, 1H, H13β), 4.73 (d, J=8.1 Hz, 1H, H10α), 6.80 (d,J=8.6 Hz, 2H, H2′), 7.29 (d, J=8.6 Hz, 2H, H1′); ¹³C NMR (100 MHz,CDCl₃) δ (ppm): −5.1, −4.1, 4.8, 6.8, 14.9, 18.1, 19.0, 25.9, 26.6,28.1, 29.4, 29.7, 37.1, 41.2, 45.5, 53.0, 55.2, 67.1, 69.8, 70.6, 95.5,113.7, 129.3, 130.4, 137.1, 137.5, 159.1, 210.2.

[0144] Ketone 29 (P₂=H, P₉=TMS, P₁₀=TES, P₁₃=TBS).

[0145] To a mixture of 1.07 g (1.5 mmol) of ketone 29 (P₂=PMB, P₉=TMS,P₁₀=TES, P₁₃=TBS) in 137.5 ml of dichloromethane/water (9:1) at 0° C.was added 1.03 g (4.5 mmol) of DDQ. The resulting mixture was stirred at0° C. for 4 h then diluted by 20 ml of ethyl acetate and washed by 3×50ml of a 1:1 solution of NaHCO₃/Na₂S₂O₃. The combined aqueous layers wereextracted by 100 ml of ethyl acetate. The organic layer was dried overNa₂SO₄ and concentrated to afford 1.04 g of the crude ketone 29 (P₂=H,P₉=TMS, P₁₀=TES, P₁₃=TBS) as a colorless oil. ¹H NMR (400 MHz, C₆D₆), δ(ppm): 0.008 (s, 3H, CH₃ 13-TBS), 0.09 (s, 3H, CH₃ 13-TBS), 0.18 (s, 9H,CH₃ 9-TMS), 0.68 (q, J=7.9 Hz, 6H, CH₂ 10-TES), 1.01 (t, J=7.9 Hz, 9H,CH₃ 10-TES), 1.04 (s, 3H, 17Me), 1.05 (d, J=7.3 Hz, 3H, 19Me), 1.06 (s,9H, (CH₃)₃ 13-TBS), 1.57 (s, 3H, 16Me), 1.79 (s, 3H, 18Me), 2.00 (dd,J=7.5, 3.7 Hz, 1H, H1), 2.13 (dd, J=15.3, 4.9 Hz, 1H, H14α), 2.26 (ddd,J=15.3, 10.4, 7.5 Hz, 1H, H₁₄β), 2.47 (dq, J=11, 7.3 Hz, 1H, H8α), 3.45(d, J=7.9 Hz, 1H, 2-OH), 4.22 (dd, J=11, 8.6 Hz, 1H, H9β), 4.40 (dd,J=10.4, 4.9 Hz, 1H, H13β), 4.46 (dd, J=7.9, 3.7 Hz, 1H, H2β), 4.66 (d,J=8.6 Hz, 1H, H10α).

[0146] Ketone 29 (P₂=P₉=TMS, P₁₀=TES, P₁₃=TBS).

[0147] To a solution of 1.04 g of crude 29 (P₂=H, P₉=TMS, P₁₀=TES,P₁₃=TBS) in 10 ml of pyridine was added a catalytic amount of DMAP andat −10° C. 420 μl (3.3 mmol) of TMSCl. After 1 h of reaction at 0° C.,the mixture was diluted by 100 ml of hexane and washed twice with 20 mlof a saturated aqueous solution of NaHCO₃. The organic layer was thendried over Na₂SO₄ and concentrated. After flash chromatography(hexane/ethyl acetate 99.5:0.5), 856 mg (86% over 2 steps) of ketone 29(P₂=P₉=TMS, P₁₀=TES, P₁₃=TBS) was obtained as a yellow oil. ¹H NMR (500MHz, C₆D₆), δ (ppm): 0.03 (s, 3H, CH₃ 13-TBS), 0.13 (s, 3H, CH₃ 13-TBS),0.15 (s, 9H, CH₃ 2-TMS), 0.24 (s, 9H, CH₃ 9-TMS), 0.72 (dq, J=7.9, 2.7Hz, 6H, CH₂ 10-TES), 1.04 (t, J=7.9 Hz, 9H, CH₃ 10-TES), 1.05 (s, 9H,(CH₃)₃ 13-TBS), 1.12 (s, 3H, 17Me), 1.19 (d, J=7.3 Hz, 3H, 19Me), 1.72(s, 3H, 16Me), 1.86 (d, J=1.2 Hz, 3H, 18Me), 1.89 (dd, J=8.2, 3.4 Hz,1H, H1), 2.30 (ddd, J=14.6, 10.3, 8.2 Hz, 1H, H14,), 2.44 (dq, J=10.7,7.3 Hz, 1H, H8α), 2.68 (dd, J=14.6, 5.5 Hz, 1H, H14α), 4.35 (dd, J=10.7,8.9 Hz, 1H, H9β), 4.54 (ddd, J=10.4, 5.5, 1.2 Hz, 1H, H13β), 4.66 (d,J=3.4 Hz, 1H, H2β), 4.72 (d, J=8.9 Hz, 1H, H10α).

[0148] In view of the above, it will be seen that the several objects ofthe invention are achieved.

[0149] As various changes could be made in the above compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A process for the preparation of a compositionhaving the formula:

the process comprising treating a compound having the formula:

with a base and a silylating agent.
 2. The process of claim 1 whereinthe base is selected from the group consisting of hydride bases andamide bases.
 3. The process of claim 1 wherein the base is selected fromthe group consisting of potassium hydride and potassiumhexamethyldisilazide.
 4. The process of claim 1 wherein the silylatingagent is a tri(hydrocarbyl)silyl halide.
 5. The process of claim 1wherein the silylating agent is a trialkylsilyl halide, said alkylgroups containing from one to four carbon atoms.
 6. The process of claim1 wherein the silylating agent is triethylsilyl chloride.
 7. The processof claim 1 wherein the base is selected from the group consisting ofhydride bases and amide bases and the silylating agent is atrialkylsilyl halide, said alkyl groups containing from one to fourcarbon atoms.
 8. The process of claim 1 wherein the base is selectedfrom the group consisting of potassium hydride and potassiumhexamethyldisilazide and the silylating agent is triethylsilyl chloride.9. A process for the preparation of a compound having the formula:

the process comprising treating a compound having the formula:

with an alkyl metal species or with a Lewis acid in the presence of atertiary amine base, wherein P₂ is hydrogen or a hydroxyl protectinggroup.
 10. The process of claim 9 wherein the compound having theformula:

is reacted with an alkyl metal species.
 11. The process of claim 10wherein the alkyl metal species is tert-butyllithium.
 12. The process ofclaim 9 wherein the compound having the formula:

is reacted with a Lewis acid.
 13. The process of claim 12 wherein theLewis acid is TMSOTf.
 14. The process of claim 9 wherein the tertiaryamine base is triethyl amine.
 15. The process of claim 9 wherein thecompound having the formula:

is treated with an alkyllithium species.
 16. The process of claim 9wherein the compound having the formula:

is reacted with TMSOTf in the presence of triethylamine.
 17. A processfor the preparation of a compound having the formula:

the process comprising treating a compound having the formula:

with a Lewis acid in the presence of a tertiary amine base, wherein P₂is hydrogen or a hydroxy protecting group.
 18. The process of claim 17wherein the Lewis acid is TMSOTf.
 19. The process of claim 17 whereinthe tertiary amine base is triethyl amine.
 20. The process of claim 17wherein the Lewis acid is TMSOTf and the tertiary amine base istriethylamine.
 21. A compound selected from the group consisting of:

wherein P₂, P₇, P₉, P₁₀ and P₁₃ are independently selected from hydrogenand hydroxy protecting group.